Compounds and compositions for treating conditions associated with nlrp activity

ABSTRACT

In one aspect, compounds of Formula AA, or a pharmaceutically acceptable salt thereof, are featured. The variables shown in Formula AA are as defined in the claims. The compounds of formula AA are NLRP3 activity modulators and, as such, can be used in the treatment of metabolic disorders (e.g. Type 2 diabetes, atherosclerosis, obesity or gout), a disease of the central nervous system (e.g. Alzheimer&#39;s disease, multiple sclerosis, Amyotrophic Lateral Sclerosis or Parkinson&#39;s disease), lung disease (e.g. asthma, COPD or pulmonary idiopathic fibrosis), liver disease (e.g. NASH syndrome, viral hepatitis or cirrhosis), pancreatic disease (e.g. acute pancreatitis or chronic pancreatitis), kidney disease (e.g. acute kidney injury or chronic kidney injury), intestinal disease (e.g. Crohn&#39;s disease or Ulcerative Colitis), skin disease (e.g. psoriasis), musculoskeletal disease (e.g. scleroderma), a vessel disorder (e.g. giant cell arteritis), a disorder of the bones (e.g. osteoarthritis, osteoporosis or osteopetrosis disorders), eye disease (e.g. glaucoma or macular degeneration), a disease caused by viral infection (e.g. HIV or AIDS), an autoimmune disease (e.g. Rheumatoid Arthritis, Systemic Lupus Erythematosus or Autoimmune Thyroiditis), cancer or aging.

PRIORITY CLAIM

This application claims the benefit of U.S. Provisional Application No.62/536,271, filed on Jul. 24, 2017; and U.S. Provisional Application No.62/573,894, filed on Oct. 18, 2017; which are both incorporated hereinby reference in their entirety.

TECHNICAL FIELD

This disclosure features chemical entities (e.g., a compound thatmodulates (e.g., antagonizes) NLRP3, or a pharmaceutically acceptablesalt, and/or hydrate, and/or cocrystal, and/or drug combination of thecompound) that are useful, e.g., for treating a condition, disease ordisorder in which a decrease or increase in NLRP3 activity (e.g., anincrease, e.g., a condition, disease or disorder associated with NLRP3signaling) contributes to the pathology and/or symptoms and/orprogression of the condition, disease or disorder in a subject (e.g., ahuman). This disclosure also features compositions as well as othermethods of using and making the same.

BACKGROUND

The NLRP3 inflammasome is a component of the inflammatory process andits aberrant activation is pathogenic in inherited disorders such as thecryopyrin associated periodic syndromes (CAPS). The inherited CAPSMuckle-Wells syndrome (MWS), familial cold autoinflammatory syndrome(FCAS) and neonatal onset multi-system inflammatory disease (NOMID) areexamples of indications that have been reported to be associated withgain of function mutations in NLRP3.

NLRP3 can form a complex and has been implicated in the pathogenesis ofa number of complex diseases, including but not limited to metabolicdisorders such as type 2 diabetes, atherosclerosis, obesity and gout, aswell as diseases of the central nervous system, such as Alzheimer'sdisease and multiple sclerosis and Amyotrophic Lateral Sclerosis andParkinson disease, lung disease, such as asthma and COPD and pulmonaryidiopathic fibrosis, liver disease, such as NASH syndrome, viralhepatitis and cirrhosis, pancreatic disease, such as acute and chronicpancreatitis, kidney disease, such as acute and chronic kidney injury,intestinal disease such as Crohn's disease and Ulcerative Colitis, skindisease such as psoriasis, musculoskeletal disease such as scleroderma,vessel disorders, such as giant cell arteritis, disorders of the bones,such as Osteoarthritis, osteoporosis and osteopetrosis disorders eyedisease, such as glaucoma and macular degeneration, diseased caused byviral infection such as HIV and AIDS, autoimmune disease such asRheumatoid Arthritis, Systemic Lupus Erythematosus, AutoimmuneThyroiditis, Addison's disease, pernicious anemia, cancer and aging.

In light of the above, it would be desirable to provide compounds thatmodulate (e.g., antagonize) NLRP3.

SUMMARY

This disclosure features chemical entities (e.g., a compound thatmodulates (e.g., antagonizes) NLRP3, or a pharmaceutically acceptablesalt, and/or hydrate, and/or cocrystal, and/or drug combination of thecompound) that are useful, e.g., for treating a condition, disease ordisorder in which a decrease or increase in NLRP3 activity (e.g., anincrease, e.g., a condition, disease or disorder associated with NLRP3signaling).

In some embodiments, provided herein is a compound of Formula AA

or a pharmaceutically acceptable salt thereof, wherein the variables inFormula AA can be as defined anywhere herein.

This disclosure also features compositions as well as other methods ofusing and making the same.

An “antagonist” of NLRP3 includes compounds that inhibit the ability ofNLRP3 to induce the production of IL-1β and/or IL-18 by directly bindingto NLRP3, or by inactivating, destabilizing, altering distribution, ofNLRP3 or otherwise.

In one aspect, pharmaceutical compositions are featured that include achemical entity described herein (e.g., a compound described genericallyor specifically herein or a pharmaceutically acceptable salt thereof orcompositions containing the same) and one or more pharmaceuticallyacceptable excipients.

In one aspect, methods for modulating (e.g., agonizing, partiallyagonizing, antagonizing) NLRP3 activity are featured that includecontacting NLRP3 with a chemical entity described herein (e.g., acompound described generically or specifically herein or apharmaceutically acceptable salt thereof or compositions containing thesame). Methods include in vitro methods, e.g., contacting a sample thatincludes one or more cells comprising NLRP3, as well as in vivo methods.

In a further aspect, methods of treatment of a disease in which NLRP3signaling contributes to the pathology and/or symptoms and/orprogression of the disease are featured that include administering to asubject in need of such treatment an effective amount of a chemicalentity described herein (e.g., a compound described generically orspecifically herein or a pharmaceutically acceptable salt thereof orcompositions containing the same).

In a further aspect, methods of treatment are featured that includeadministering to a subject a chemical entity described herein (e.g., acompound described generically or specifically herein or apharmaceutically acceptable salt thereof or compositions containing thesame), wherein the chemical entity is administered in an amounteffective to treat a disease in which NLRP3 signaling contributes to thepathology and/or symptoms and/or progression of the disease, therebytreating the disease.

Embodiments can include one or more of the following features.

The chemical entity can be administered in combination with one or moreadditional therapies with one or more agents suitable for the treatmentof the condition, disease or disorder.

Examples of the indications that may be treated by the compoundsdisclosed herein include but are not limited to metabolic disorders suchas type 2 diabetes, atherosclerosis, obesity and gout, as well asdiseases of the central nervous system, such as Alzheimer's disease andmultiple sclerosis and Amyotrophic Lateral Sclerosis and Parkinsondisease, lung disease, such as asthma and COPD and pulmonary idiopathicfibrosis, liver disease, such as NASH syndrome, viral hepatitis andcirrhosis, pancreatic disease, such as acute and chronic pancreatitis,kidney disease, such as acute and chronic kidney injury, intestinaldisease such as Crohn's disease and Ulcerative Colitis, skin diseasesuch as psoriasis, musculoskeletal disease such as scleroderma, vesseldisorders, such as giant cell arteritis, disorders of the bones, such asosteoarthritis, osteoporosis and osteopetrosis disorders, eye disease,such as glaucoma and macular degeneration, diseases caused by viralinfection such as HIV and AIDS, autoimmune disease such as rheumatoidarthritis, systemic Lupus erythematosus, autoimmune thyroiditis;Addison's disease, pernicious anemia, cancer and aging.

The methods can further include identifying the subject.

Other embodiments include those described in the Detailed Descriptionand/or in the claims.

Additional Definitions

To facilitate understanding of the disclosure set forth herein, a numberof additional terms are defined below. Generally, the nomenclature usedherein and the laboratory procedures in organic chemistry, medicinalchemistry, and pharmacology described herein are those well-known andcommonly employed in the art. Unless defined otherwise, all technicaland scientific terms used herein generally have the same meaning ascommonly understood by one of ordinary skill in the art to which thisdisclosure belongs. Each of the patents, applications, publishedapplications, and other publications that are mentioned throughout thespecification and the attached appendices are incorporated herein byreference in their entireties.

As used herein, the term “NLRP3” is meant to include, withoutlimitation, nucleic acids, polynucleotides, oligonucleotides, sense andantisense polynucleotide strands, complementary sequences, peptides,polypeptides, proteins, homologous and/or orthologous NLRP3 molecules,isoforms, precursors, mutants, variants, derivatives, splice variants,alleles, different species, and active fragments thereof.

The term “acceptable” with respect to a formulation, composition oringredient, as used herein, means having no persistent detrimentaleffect on the general health of the subject being treated.

“API” refers to an active pharmaceutical ingredient.

The terms “effective amount” or “therapeutically effective amount,” asused herein, refer to a sufficient amount of a chemical entity (e.g., acompound exhibiting activity as a modulator of NLRP3, or apharmaceutically acceptable salt and/or hydrate and/or cocrystalthereof;) being administered which will relieve to some extent one ormore of the symptoms of the disease or condition being treated. Theresult includes reduction and/or alleviation of the signs, symptoms, orcauses of a disease, or any other desired alteration of a biologicalsystem. For example, an “effective amount” for therapeutic uses is theamount of the composition comprising a compound as disclosed hereinrequired to provide a clinically significant decrease in diseasesymptoms. An appropriate “effective” amount in any individual case isdetermined using any suitable technique, such as a dose escalationstudy.

The term “excipient” or “pharmaceutically acceptable excipient” means apharmaceutically-acceptable material, composition, or vehicle, such as aliquid or solid filler, diluent, carrier, solvent, or encapsulatingmaterial. In one embodiment, each component is “pharmaceuticallyacceptable” in the sense of being compatible with the other ingredientsof a pharmaceutical formulation, and suitable for use in contact withthe tissue or organ of humans and animals without excessive toxicity,irritation, allergic response, immunogenicity, or other problems orcomplications, commensurate with a reasonable benefit/risk ratio. See,e.g., Remington: The Science and Practice of Pharmacy, 21 st ed.;Lippincott Williams & Wilkins: Philadelphia, Pa., 2005; Handbook ofPharmaceutical Excipients, 6th ed.; Rowe et al., Eds.; ThePharmaceutical Press and the American Pharmaceutical Association: 2009;Handbook of Pharmaceutical Additives, 3rd ed.; Ash and Ash Eds.; GowerPublishing Company: 2007; Pharmaceutical Preformulation and Formulation,2nd ed.; Gibson Ed.; CRC Press LLC: Boca Raton, Fla., 2009.

The term “pharmaceutically acceptable salt” may refer topharmaceutically acceptable addition salts prepared frompharmaceutically acceptable non-toxic acids including inorganic andorganic acids. In certain instances, pharmaceutically acceptable saltsare obtained by reacting a compound described herein, with acids such ashydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, methanesulfonic acid, ethanesulfonic acid,p-toluenesulfonic acid, salicylic acid and the like. The term“pharmaceutically acceptable salt” may also refer to pharmaceuticallyacceptable addition salts prepared by reacting a compound having anacidic group with a base to form a salt such as an ammonium salt, analkali metal salt, such as a sodium or a potassium salt, an alkalineearth metal salt, such as a calcium or a magnesium salt, a salt oforganic bases such as dicyclohexylamine, N-methyl-D-glucamine,tris(hydroxymethyl)methylamine, and salts with amino acids such asarginine, lysine, and the like, or by other methods previouslydetermined. The pharmacologically acceptable salt s not specificallylimited as far as it can be used in medicaments. Examples of a salt thatthe compounds described hereinform with a base include the following:salts thereof with inorganic bases such as sodium, potassium, magnesium,calcium, and aluminum; salts thereof with organic bases such asmethylamine, ethylamine and ethanolamine; salts thereof with basic aminoacids such as lysine and ornithine; and ammonium salt. The salts may beacid addition salts, which are specifically exemplified by acid additionsalts with the following: mineral acids such as hydrochloric acid,hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, andphosphoric acid:organic acids such as formic acid, acetic acid,propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid,maleic acid, lactic acid, malic acid, tartaric acid, citric acid,methanesulfonic acid, and ethanesulfonic acid; acidic amino acids suchas aspartic acid and glutamic acid.

The term “pharmaceutical composition” refers to a mixture of a compounddescribed herein with other chemical components (referred tocollectively herein as “excipients”), such as carriers, stabilizers,diluents, dispersing agents, suspending agents, and/or thickeningagents. The pharmaceutical composition facilitates administration of thecompound to an organism. Multiple techniques of administering a compoundexist in the art including, but not limited to: rectal, oral,intravenous, aerosol, parenteral, ophthalmic, pulmonary, and topicaladministration.

The term “subject” refers to an animal, including, but not limited to, aprimate (e.g., human), monkey, cow, pig, sheep, goat, horse, dog, cat,rabbit, rat, or mouse. The terms “subject” and “patient” are usedinterchangeably herein in reference, for example, to a mammaliansubject, such as a human.

The terms “treat,” “treating,” and “treatment,” in the context oftreating a disease or disorder, are meant to include alleviating orabrogating a disorder, disease, or condition, or one or more of thesymptoms associated with the disorder, disease, or condition; or toslowing the progression, spread or worsening of a disease, disorder orcondition or of one or more symptoms thereof.

The terms “hydrogen” and “H” are used interchangeably herein.

The term “halo” refers to fluoro (F), chloro (Cl), bromo (Br), or iodo(I).

The term “alkyl” refers to a hydrocarbon chain that may be a straightchain or branched chain, saturated or unsaturated, containing theindicated number of carbon atoms. For example, C₁₋₁₀ indicates that thegroup may have from 1 to 10 (inclusive) carbon atoms in it. Non-limitingexamples include methyl, ethyl, iso-propyl, tert-butyl, n-hexyl.

The term “haloalkyl” refers to an alkyl, in which one or more hydrogenatoms is/are replaced with an independently selected halo.

The term “alkoxy” refers to an —O-alkyl radical (e.g., —OCH₃).

The term “carbocyclic ring” as used herein includes an aromatic ornonaromatic cyclic hydrocarbon group having 3 to 10 carbons, such as 3to 8 carbons, such as 3 to 7 carbons, which may be optionallysubstituted. Examples of carbocyclic rings include five-membered,six-membered, and seven-membered carbocyclic rings.

The term “heterocyclic ring” refers to an aromatic or nonaromatic 5-8membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclicring system having 1-3 heteroatoms if monocyclic, 1-6 heteroatoms ifbicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selectedfrom O, N, or S (e.g., carbon atoms and 1-3, 1-6, or 1-9 heteroatoms ofN, O, or S if monocyclic, bicyclic, or tricyclic, respectively), wherein0, 1, 2, or 3 atoms of each ring may be substituted by a substituent.Examples of heterocyclic rings include five-membered, six-membered, andseven-membered heterocyclic rings.

The term “cycloalkyl” as used herein includes an nonaromatic cyclic,bicylic, fused, or spiro hydrocarbon radical having 3 to 10 carbons,such as 3 to 8 carbons, such as 3 to 7 carbons, wherein the cycloalkylgroup which may be optionally substituted. Examples of cycloalkylsinclude five-membered, six-membered, and seven-membered rings. Examplesinclude cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl,cyclohexenyl, cycloheptyl, and cyclooctyl.

The term “heterocycloalkyl” refers to an nonaromatic 5-8 memberedmonocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring,fused, or spiro system radical having 1-3 heteroatoms if monocyclic, 1-6heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, saidheteroatoms selected from O, N, or S (e.g., carbon atoms and 1-3, 1-6,or 1-9 heteroatoms of N, O, or S if monocyclic, bicyclic, or tricyclic,respectively), wherein 0, 1, 2, or 3 atoms of each ring may besubstituted by a substituent. Examples of heterocycloalkyls includefive-membered, six-membered, and seven-membered heterocyclic rings.Examples include piperazinyl, pyrrolidinyl, dioxanyl, morpholinyl,tetrahydrofuranyl, and the like.

The term “aryl” is intended to mean an aromatic ring radical containing6 to 10 ring carbons. Examples include phenyl and naphthyl.

The term “heteroaryl” is intended to mean an aromatic ring systemcontaining 5 to 14 aromatic ring atoms that may be a single ring, twofused rings or three fused rings wherein at least one aromatic ring atomis a heteroatom selected from, but not limited to, the group consistingof O, S and N. Examples include furanyl, thienyl, pyrrolyl, imidazolyl,oxazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, oxadiazolyl,triazolyl, thiadiazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl,triazinyl and the like. Examples also include carbazolyl, quinolizinyl,quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl,quinoxalinyl, triazinyl, indolyl, isoindolyl, indazolyl, indolizinyl,purinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl,phenothiazinyl, phenoxazinyl, benzoxazolyl, benzothiazolyl,1H-benzimidazolyl, imidazopyridinyl, benzothienyl, benzofuranyl,isobenzofuran and the like.

The term “hydroxy” refers to an OH group.

The term “amino” refers to an NH₂ group.

The term “oxo” refers to O. By way of example, substitution of a CH₂ agroup with oxo gives a C═O group.

As used herein, the terms “the ring A” or “A” are used interchangeablyto denote

in formula AA, wherein the bond that is shown as being broken by thewavy line

connects A to the S(O)(NHR³)═N moiety of Formula AA.

As used herein, the terms “the ring B” or “B” are used interchangeablyto denote

in formula AA wherein the bond that is shown as being broken by the wavyline

connects B to the NH(CO) group of Formula AA.

As used herein, the term “the optionally substituted ring A” is used todenote

in formula AA, wherein the bond that is shown as being broken by thewavy line

connects A to the S(O)(NHR³)═N moiety of Formula AA.

As used herein, the term “the substituted ring B” is used to denote

in formula AA, wherein the bond that is shown as being broken by thewavy line

connects B to the NH(CO) group of Formula AA.

As used herein, the recitation “S(O₂)”, alone or as part of a largerrecitation, refers to the group

In addition, atoms making up the compounds of the present embodimentsare intended to include all isotopic forms of such atoms. Isotopes, asused herein, include those atoms having the same atomic number butdifferent mass numbers. By way of general example and withoutlimitation, isotopes of hydrogen include tritium and deuterium, andisotopes of carbon include ¹³C and ¹⁴C.

The scope of the compounds disclosed herein includes tautomeric form ofthe compounds. Thus, by way of example, a compound that is representedas containing the moiety

is also intended to include the tautomeric form containing the moiety

In addition, by way of example, a compound that is represented ascontaining the moiety

is also intended to include the tautomeric form containing the moiety

Non-limiting exemplified compounds of the formulae described hereininclude a stereogenic sulfur atom and optionally one or more stereogeniccarbon atoms. This disclosure provides examples of stereoisomer mixtures(e.g., racemic mixture of enantiomers; mixture of diastereomers). Thisdisclosure also describes and exemplifies methods for separatingindividual components of said stereoisomer mixtures (e.g., resolving theenantiomers of a racemic mixture). In cases of compounds containing onlya stereogenic sulfur atom, resolved enantiomers are graphically depictedusing one of the two following formats: formulas A/B (hashed and solidwedge three-dimensional representation); and formula C (“flat structureswith *-labelled stereogenic sulfur).

In reaction schemes showing resolution of a racemic mixture, FormulasA/B and C are intended only to convey that the constituent enantiomerswere resolved in enantiopure pure form (about 98% ee or greater). Theschemes that show resolution products using the formula A/B format arenot intended to disclose or imply any correlation between absoluteconfiguration and order of elution. Some of the compounds shown in thetables below are graphically represented using the formula A/B format.However, with the exception of compounds 181a and 181b, the depictedstereochemistry shown for each of the tabulated compounds drawn in theformula A/B format is a tentative assignment and based, by analogy, onthe absolute stereochemistry assigned to compounds 181b (see, e.g.,FIGS. 1 and 2).

The details of one or more embodiments of the invention are set forth inthe accompanying drawings and the description below. Other features andadvantages of the invention will be apparent from the description anddrawings, and from the claims.

DESCRIPTION OF DRAWINGS

FIG. 1 depicts ball-and-stick representations of twocrystallographically independent molecules of compound 181a in theasymmetrical unit.

FIG. 2 depicts ball-and-stick representations of twocrystallographically independent molecules of compound 181b in theasymmetrical unit.

FIG. 3 depicts the layout of the microplate used in an hTHP-1 assay.

DETAILED DESCRIPTION

In some embodiments, provided herein is a compound of Formula AA

whereinm=0, 1, or 2;n=0, 1, or 2;o=1 or 2;p=0, 1, 2, or 3;whereinA is a 5-10-membered heteroaryl or a C₆-C₁₀ aryl;B is a 5-10-membered heteroaryl or a C₆-C₁₀ aryl;whereinat least one R⁶ is ortho to the bond connecting the B ring to theNR³(CO) group of Formula AA;R¹ and R² are each independently selected from C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halo, CN, NO₂, COC₁-C₆ alkyl,CO—C₆-C₁₀ aryl, CO-(5- to 10-membered heteroaryl), CO₂C₁-C₆ alkyl,CO₂C₃-C₈ cycloalkyl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO (5- to10-membered heteroaryl), OCO (3- to 7-membered heterocycloalkyl), C₆-C₁₀aryl, 5- to 10-membered heteroaryl, NH₂, NHC₁-C₆ alkyl, N(C₁-C₆ alkyl)₂,NHCOC₁-C₆ alkyl, NHCOC₆-C₁₀ aryl, NHCO (5- to 10-membered heteroaryl),NHCO (3- to 7-membered heterocycloalkyl), NHCOC₂-C₆ alkynyl, NHCOOC₁-C₆alkyl, NH—(C═NR¹³)NR¹¹R¹², CONR⁸R⁹, SF₅, SC₁-C₆ alkyl, S(O₂)C₁-C₆ alkyl,S(O₂)NR¹¹R¹², S(O)C₁-C₆ alkyl, C₃-C₇ cycloalkyl, and 3- to 7-memberedheterocycloalkyl,wherein the C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₇ cycloalkyl, and 3- to7-membered heterocycloalkyl is optionally substituted with one or moresubstituents each independently selected from hydroxy, halo, CN, oxo,C₁-C₆ alkyl, C₁-C₆ alkoxy, COOC₁-C₆ alkyl, NR⁸R⁹, CONR⁸R⁹, 3- to7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl,OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO (5- to 10-membered heteroaryl), andOCO (3- to 7-membered heterocycloalkyl), NHCOC₁-C₆ alkyl, NHCOC₆-C₁₀aryl, NHCO (5- to 10-membered heteroaryl), NHCO (3- to 7-memberedheterocycloalkyl), and NHCOC₂-C₆ alkynyl;

-   -   wherein each C₁-C₆ alkyl substituent and each C₁-C₆ alkoxy        substituent of the R¹ or R² C₃-C₇ cycloalkyl or of the R¹ or R²        3- to 7-membered heterocycloalkyl is further optionally        independently substituted with one to three hydroxy, halo, or        oxo;    -   wherein the 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, or        5- to 10-membered heteroaryl, of the R¹ or R² C₁-C₆ alkyl, the        R¹ or R² C₁-C₆ haloalkyl, the R¹ or R² C₃-C₇ cycloalkyl, or the        R¹ or R² 3- to 7-membered heterocycloalkyl are optionally        substituted with one or more substituents independently selected        from halo, C₁-C₆ alkyl, oxo, and OC₁-C₆ alkyl;        or at least one pair of R¹ and R² on adjacent atoms, taken        together with the atoms connecting them, independently form at        least one C₄-C₈ carbocyclic ring or at least one 5-        to-8-membered heterocyclic ring containing 1 or 2 heteroatoms        independently selected from O, N, and S, wherein the carbocyclic        ring or heterocyclic ring is optionally independently        substituted with one or more substituents independently selected        from hydroxy, halo, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹,        ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹, wherein the        C₁-C₆ alkyl and C₁-C₆ alkoxy are optionally substituted with        hydroxy, halo, oxo, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹;        R⁶ and R⁷ are each independently selected from C₁-C₆ alkyl,        C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halo, CN, NO₂,        COC₁-C₆ alkyl, CO₂C₁-C₆ alkyl, CO₂C₃-C₈ cycloalkyl, OCOC₁-C₆        alkyl, OCOC₆-C₁₀ aryl, OCO (5- to 10-membered heteroaryl), OCO        (3- to 7-membered heterocycloalkyl), C₆-C₁₀ aryl, 5- to        10-membered heteroaryl, NH₂, NHC₁-C₆ alkyl, N(C₁-C₆ alkyl)₂,        CONR⁸R⁹, SF₅, SC₁-C₆ alkyl, S(O₂)C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl,        3- to 10-membered heterocycloalkyl, and C₂-C₆ alkenyl,        wherein R⁶ and R⁷ are each optionally substituted with one or        more substituents independently selected from hydroxy, halo, CN,        oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl,        CONR⁸R⁹, 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to        10-membered heteroaryl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO (5-        to 10-membered heteroaryl), OCO (3- to 7-membered        heterocycloalkyl), NHCOC₁-C₆ alkyl, NHCOC₆-C₁₀ aryl, NHCO (5- to        10-membered heteroaryl), NHCO (3- to 7-membered        heterocycloalkyl), NHCOC₂-C₆ alkynyl, C₆-C₁₀ aryloxy, and        S(O₂)C₁-C₆ alkyl; and wherein the C₁-C₆ alkyl or C₁-C₆ alkoxy        that R⁶ or R⁷ is substituted with is optionally substituted with        one or more hydroxyl, halo, C₆-C₁₀ aryl or NR⁸R⁹, or wherein R⁶        or R⁷ is optionally fused to a five- to -seven-membered        carbocyclic ring or heterocyclic ring containing one or two        heteroatoms independently selected from oxygen, sulfur and        nitrogen;    -   wherein the 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5-        to 10-membered heteroaryl, NHCOC₆-C₁₀ aryl, NHCO (5- to        10-membered heteroaryl) and NHCO (3- to 7-membered        heterocycloalkyl) are optionally substituted with one or more        substituents independently selected from halo, C₁-C₆ alkyl, and        OC₁-C₆ alkyl;        or at least one pair of R⁶ and R⁷ on adjacent atoms, taken        together with the atoms connecting them, independently form at        least one C₄-C₈ carbocyclic ring or at least one 4- to        8-membered heterocyclic ring containing 1 or 2 heteroatoms        independently selected from O, N, NR²⁰, and S, wherein the        carbocyclic ring or heterocyclic ring is optionally        independently substituted with one or more substituents        independently selected from hydroxy, hydroxymethyl, halo, oxo,        C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, CH₂NR⁸R⁹, ═NR¹⁰, COOC₁-C₆        alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹; each of R⁴ and R⁵ is        independently selected from hydrogen and C₁-C₆ alkyl;        R¹⁰ is C₁-C₆ alkyl;        each of R⁸ and R⁹ at each occurrence is independently selected        from hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,        (C═NR¹³)NR¹¹R¹², S(O₂)C₁-C₆ alkyl, S(O₂)NR¹¹R¹², COR¹³, CO₂R¹³        and CONR¹¹R¹²; wherein the C₁-C₆ alkyl, C₂-C₆ alkenyl, or C₂-C₆        alkynyl is optionally substituted with one or more hydroxy,        halo, oxo, C₁-C₆ alkoxy, C₂-C₆ alkynyl, CO₂R¹³, C₆-C₁₀ aryl, 5-        to 10-membered heteroaryl, C₃-C₇ cycloalkyl, or 3- to 7-membered        heterocycloalkyl; or        R⁸ and R⁹ taken together with the nitrogen they are attached to        form a 3- to 7-membered ring optionally containing one or more        heteroatoms in addition to the nitrogen they are attached to;        R¹³ is C₁-C₆ alkyl, C₆-C₁₀ aryl, or 5- to 10-membered        heteroaryl;        each of R¹¹ and R¹² at each occurrence is independently selected        from hydrogen and C₁-C₆ alkyl;        each R³ is independently selected from hydrogen, cyano, hydroxy,        C₁-C₆ alkoxy, C₁-C₆ alkyl, CO₂C₁-C₆ alkyl, and

wherein the C₁-C₂ alkylene group is optionally substituted with oxo; andR¹¹ is hydrogen, C₁-C₆ alkyl, 5-10-membered monocyclic or bicyclicheteroaryl or C₆-C₁₀ monocyclic or bicyclic aryl, wherein each C₁-C₆alkyl, aryl or heteroaryl is optionally independently substituted with1, 2, or 3 R⁶;or a pharmaceutically acceptable salt thereof.

In some embodiments, provided herein is a compound of Formula AA

whereinm=0, 1, or 2;n=0, 1, or 2;o=1 or 2;p=0, 1, 2, or 3;whereinA is a 5-10-membered heteroaryl or a C₆-C₁₀ aryl;B is a 5-10-membered heteroaryl or a C₆-C₁₀ aryl;whereinat least one R⁶ is ortho to the bond connecting the B ring to theNR³(CO) group of Formula AA; R¹ and R² are each independently selectedfrom C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halo,CN, NO₂, COC₁-C₆ alkyl, CO—C₆-C₁₀ aryl, CO-(5- to 10-memberedheteroaryl), CO₂C₁-C₆ alkyl, CO₂C₃-C₈ cycloalkyl, OCOC₁-C₆ alkyl,OCOC₆-C₁₀ aryl, OCO (5- to 10-membered heteroaryl), OCO (3- to7-membered heterocycloalkyl), C₆-C₁₀ aryl, 5- to 10-membered heteroaryl,NH₂, NHC₁-C₆ alkyl, N(C₁-C₆ alkyl)₂, NHCOC₁-C₆ alkyl, NHCOC₆-C₁₀ aryl,NHCO (5- to 10-membered heteroaryl), NHCO (3- to 7-memberedheterocycloalkyl), NHCOC₂-C₆ alkynyl, NHCOOC₁-C₆ alkyl,NH—(C═NR¹³)NR¹¹R¹², CONR⁸R⁹, SF₅, SC₁-C₆ alkyl, S(O₂)C₁-C₆ alkyl,S(O₂)NR¹¹R¹², S(O)C₁-C₆ alkyl, C₃-C₇ cycloalkyl, and 3- to 7-memberedheterocycloalkyl,wherein the C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₇ cycloalkyl, and 3- to7-membered heterocycloalkyl is optionally substituted with one or moresubstituents each independently selected from hydroxy, halo, CN, oxo,C₁-C₆ alkyl, C₁-C₆ alkoxy, COOC₁-C₆ alkyl, NR⁸R⁹, CONR⁸R⁹, 3- to7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl,OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO (5- to 10-membered heteroaryl), andOCO (3- to 7-membered heterocycloalkyl), NHCOC₁-C₆ alkyl, NHCOC₆-C₁₀aryl, NHCO (5- to 10-membered heteroaryl), NHCO (3- to 7-memberedheterocycloalkyl), and NHCOC₂-C₆ alkynyl;

-   -   wherein each C₁-C₆ alkyl substituent and each C₁-C₆ alkoxy        substituent of the R¹ or R² C₃-C₇ cycloalkyl or of the R¹ or R²        3- to 7-membered heterocycloalkyl is further optionally        independently substituted with one to three hydroxy, halo, or        oxo;    -   wherein the 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, or        5- to 10-membered heteroaryl, of the R¹ or R² C₁-C₆ alkyl, the        R¹ or R² C₁-C₆ haloalkyl, the R¹ or R² C₃-C₇ cycloalkyl, or the        R¹ or R² 3- to 7-membered heterocycloalkyl are optionally        substituted with one or more substituents independently selected        from halo, C₁-C₆ alkyl, oxo, and OC₁-C₆ alkyl;        or at least one pair of R¹ and R² on adjacent atoms, taken        together with the atoms connecting them, independently form at        least one C₄-C₈ carbocyclic ring or at least one 5-        to-8-membered heterocyclic ring containing 1 or 2 heteroatoms        independently selected from O, N, and S, wherein the carbocyclic        ring or heterocyclic ring is optionally independently        substituted with one or more substituents independently selected        from hydroxy, halo, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹,        ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹, wherein the        C₁-C₆ alkyl and C₁-C₆ alkoxy are optionally substituted with        hydroxy, halo, oxo, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹;        R⁶ and R⁷ are each independently selected from C₁-C₆ alkyl,        C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halo, CN, NO₂,        COC₁-C₆ alkyl, CO₂C₁-C₆ alkyl, CO₂C₃-C₈ cycloalkyl, OCOC₁-C₆        alkyl, OCOC₆-C₁₀ aryl, OCO (5- to 10-membered heteroaryl), OCO        (3- to 7-membered heterocycloalkyl), C₆-C₁₀ aryl, 5- to        10-membered heteroaryl, NH₂, NHC₁-C₆ alkyl, N(C₁-C₆ alkyl)₂,        CONR⁸R⁹, SF₅, SC₁-C₆ alkyl, S(O₂)C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl,        3- to 10-membered heterocycloalkyl, and C₂-C₆ alkenyl,        wherein R⁶ and R⁷ are each optionally substituted with one or        more substituents independently selected from hydroxy, halo, CN,        oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl,        CONR⁸R⁹, 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to        10-membered heteroaryl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO (5-        to 10-membered heteroaryl), OCO (3- to 7-membered        heterocycloalkyl), NHCOC₁-C₆ alkyl, NHCOC₆-C₁₀ aryl, NHCO (5- to        10-membered heteroaryl), NHCO (3- to 7-membered        heterocycloalkyl), NHCOC₂-C₆ alkynyl, C₆-C₁₀ aryloxy, and        S(O₂)C₁-C₆ alkyl; and wherein the C₁-C₆ alkyl or C₁-C₆ alkoxy        that R⁶ or R⁷ is substituted with is optionally substituted with        one or more hydroxyl, halo, C₆-C₁₀ aryl or NR⁸R⁹, or wherein R⁶        or R⁷ is optionally fused to a five- to -seven-membered        carbocyclic ring or heterocyclic ring containing one or two        heteroatoms independently selected from oxygen, sulfur and        nitrogen;    -   wherein the 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5-        to 10-membered heteroaryl, NHCOC₆-C₁₀ aryl, NHCO (5- to        10-membered heteroaryl) and NHCO (3- to 7-membered        heterocycloalkyl) are optionally substituted with one or more        substituents independently selected from halo, C₁-C₆ alkyl, and        OC₁-C₆ alkyl;        or at least one pair of R⁶ and R⁷ on adjacent atoms, taken        together with the atoms connecting them, independently form at        least one C₄-C₈ carbocyclic ring or at least one 5- to        8-membered heterocyclic ring containing 1 or 2 heteroatoms        independently selected from O, N, and S, wherein the carbocyclic        ring or heterocyclic ring is optionally independently        substituted with one or more substituents independently selected        from hydroxy, hydroxymethyl, halo, oxo, C₁-C₆ alkyl, C₁-C₆        alkoxy, NR⁸R⁹, CH₂NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and        CONR⁸R⁹;        R¹⁰ is C₁-C₆ alkyl;        each of R⁸ and R⁹ at each occurrence is independently selected        from hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,        (C═NR¹³)NR¹¹R¹², S(O₂)C₁-C₆ alkyl, S(O₂)NR¹¹R¹², COR¹³, CO₂R¹³        and CONR¹¹R¹²; wherein the C₁-C₆ alkyl, C₂-C₆ alkenyl, or C₂-C₆        alkynyl is optionally substituted with one or more hydroxy,        halo, oxo, C₁-C₆ alkoxy, C₂-C₆ alkynyl, CO₂R¹³, C₆-C₁₀ aryl, 5-        to 10-membered heteroaryl, C₃-C₇ cycloalkyl, or 3- to 7-membered        heterocycloalkyl; or        R⁸ and R⁹ taken together with the nitrogen they are attached to        form a 3- to 7-membered ring optionally containing one or more        heteroatoms in addition to the nitrogen they are attached to;        R¹³ is C₁-C₆ alkyl, C₆-C₁₀ aryl, or 5- to 10-membered        heteroaryl;        each of R¹¹ and R¹² at each occurrence is independently selected        from hydrogen and C₁-C₆ alkyl;        each R³ is independently selected from hydrogen, cyano, hydroxy,        C₁-C₆ alkoxy, C₁-C₆ alkyl, CO₂C₁-C₆ alkyl, and

wherein the C₁-C₂ alkylene group is optionally substituted with oxo; andR¹⁴ is hydrogen, C₁-C₆ alkyl, 5-10-membered monocyclic or bicyclicheteroaryl or C₆-C₁₀ monocyclic or bicyclic aryl, wherein each C₁-C₆alkyl, aryl or heteroaryl is optionally independently substituted with1, 2, or 3 R⁶;or a pharmaceutically acceptable salt thereof.

In some embodiments, provided herein is a compound of Formula AA

whereinm=0, 1, or 2;n=0, 1, or 2;o=1 or 2;p=0, 1, 2, or 3;whereinA is a 5-10-membered heteroaryl or a C₆-C₁₀ aryl;B is a 5-10-membered heteroaryl or a C₆-C₁₀ aryl;whereinat least one R⁶ is ortho to the bond connecting the B ring to theNR³(CO) group of Formula AA;R¹ and R² are each independently selected from C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halo, CN, NO₂, COC₁-C₆ alkyl,CO—C₆-C₁₀ aryl, CO-(5- to 10-membered heteroaryl), CO₂C₁-C₆ alkyl,CO₂C₃-C₈ cycloalkyl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO (5- to10-membered heteroaryl), OCO (3- to 7-membered heterocycloalkyl), C₆-C₁₀aryl, 5- to 10-membered heteroaryl, NH₂, NHC₁-C₆ alkyl, N(C₁-C₆ alkyl)₂,NHCOC₁-C₆ alkyl, NHCOC₆-C₁₀ aryl, NHCO (5- to 10-membered heteroaryl),NHCO (3- to 7-membered heterocycloalkyl), NHCOC₂-C₆ alkynyl, NHCOOC₁-C₆alkyl, NH—(C═NR¹³)NR¹¹R¹², CONR⁸R⁹, SF₅, SC₁-C₆ alkyl, S(O₂)C₁-C₆ alkyl,S(O₂)NR¹¹R¹², S(O)C₁-C₆ alkyl, C₃-C₇ cycloalkyl, and 3- to 7-memberedheterocycloalkyl,wherein the C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₇ cycloalkyl, and 3- to7-membered heterocycloalkyl is optionally substituted with one or moresubstituents each independently selected from hydroxy, halo, CN, oxo,C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, CONR⁸R⁹, 3- to7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl,OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO (5- to 10-membered heteroaryl), andOCO (3- to 7-membered heterocycloalkyl), NHCOC₁-C₆ alkyl, NHCOC₆-C₁₀aryl, NHCO (5- to 10-membered heteroaryl), NHCO (3- to 7-memberedheterocycloalkyl), and NHCOC₂-C₆ alkynyl;

-   -   wherein each C₁-C₆ alkyl substituent and each C₁-C₆ alkoxy        substituent of the R¹ or R² C₃-C₇ cycloalkyl or of the R¹ or R²        3- to 7-membered heterocycloalkyl is further optionally        independently substituted with one to three hydroxy, halo,        NR⁸R⁹, or oxo;    -   wherein the 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5-        to 10-membered heteroaryl, NHCOC₆-C₁₀ aryl, NHCO (5- to        10-membered heteroaryl) and NHCO (3- to 7-membered        heterocycloalkyl) are optionally substituted with one or more        substituents independently selected from halo, C₁-C₆ alkyl, and        OC₁-C₆ alkyl;        or at least one pair of R¹ and R² on adjacent atoms, taken        together with the atoms connecting them, independently form at        least one C₄-C₈ carbocyclic ring or at least one 5-        to-8-membered heterocyclic ring containing 1 or 2 heteroatoms        independently selected from O, N, and S, wherein the carbocyclic        ring or heterocyclic ring is optionally independently        substituted with one or more substituents independently selected        from hydroxy, halo, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹,        ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹, wherein the        C₁-C₆ alkyl and C₁-C₆ alkoxy are optionally substituted with        hydroxy, halo, oxo, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl,        and CONR⁸R⁹;        R⁶ and R⁷ are each independently selected from C₁-C₆ alkyl,        C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halo, CN, NO₂,        COC₁-C₆ alkyl, CO₂C₁-C₆ alkyl, CO₂C₃-C₈ cycloalkyl, OCOC₁-C₆        alkyl, OCOC₆-C₁₀ aryl, OCO (5- to 10-membered heteroaryl), OCO        (3- to 7-membered heterocycloalkyl), C₆-C₁₀ aryl, 5- to        10-membered heteroaryl, NH₂, NHC₁-C₆ alkyl, N(C₁-C₆ alkyl)₂,        CONR⁸R⁹, SF₅, SC₁-C₆ alkyl, S(O₂)C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl,        3- to 10-membered heterocycloalkyl, and C₂-C₆ alkenyl,        wherein R⁶ and R⁷ are each optionally substituted with one or        more substituents independently selected from hydroxy, halo, CN,        oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl,        CONR⁸R⁹, 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to        10-membered heteroaryl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO (5-        to 10-membered heteroaryl), OCO (3- to 7-membered        heterocycloalkyl), NHCOC₁-C₆ alkyl, NHCOC₆-C₁₀ aryl, NHCO (5- to        10-membered heteroaryl), NHCO (3- to 7-membered        heterocycloalkyl), NHCOC₂-C₆ alkynyl, C₆-C₁₀ aryloxy, and        S(O₂)C₁-C₆ alkyl; and wherein the C₁-C₆ alkyl or C₁-C₆ alkoxy        that R⁶ or R⁷ is substituted with is optionally substituted with        one or more hydroxyl, halo, C₆-C₁₀ aryl or NR⁸R⁹, or wherein R⁶        or R⁷ is optionally fused to a five- to -seven-membered        carbocyclic ring or heterocyclic ring containing one or two        heteroatoms independently selected from oxygen, sulfur and        nitrogen and optionally substituted with halo;    -   wherein the 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5-        to 10-membered heteroaryl, NHCOC₆-C₁₀ aryl, NHCO (5- to        10-membered heteroaryl) and NHCO (3- to 7-membered        heterocycloalkyl) are optionally substituted with one or more        substituents independently selected from halo, C₁-C₆ alkyl, and        OC₁-C₆ alkyl;        or at least one pair of R⁶ and R⁷ on adjacent atoms, taken        together with the atoms connecting them, independently form at        least one C₄-C₈ carbocyclic ring or at least one 5- to        8-membered heterocyclic ring containing 1 or 2 heteroatoms        independently selected from O, N, and S, wherein the carbocyclic        ring or heterocyclic ring is optionally independently        substituted with one or more substituents independently selected        from hydroxy, hydroxymethyl, halo, oxo, C₁-C₆ alkyl, C₁-C₆        alkoxy, NR⁸R⁹, CH₂NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and        CONR⁸R⁹;        R¹⁰ is C₁-C₆ alkyl;        each of R⁸ and R⁹ at each occurrence is independently selected        from hydrogen, C₁-C₆ alkyl, (C═NR¹³)NR¹¹R¹², S(O₂)C₁-C₆ alkyl,        S(O₂)NR¹¹R¹², COR¹³, CO₂R¹³ and CONR¹¹R¹²; wherein the C₁-C₆        alkyl is optionally substituted with one or more hydroxy, halo,        C₁-C₆ alkoxy, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₇        cycloalkyl or 3- to 7-membered heterocycloalkyl; or        R⁸ and R⁹ taken together with the nitrogen they are attached to        form a 3- to 7-membered ring optionally containing one or more        heteroatoms in addition to the nitrogen they are attached to;        R¹³ is C₁-C₆ alkyl, C₆-C₁₀ aryl, or 5- to 10-membered        heteroaryl;        each of R¹¹ and R¹² at each occurrence is independently selected        from hydrogen and C₁-C₆ alkyl; R³ is selected from hydrogen,        cyano, hydroxy, C₁-C₆ alkoxy, C₁-C₆ alkyl, CO₂C₁-C₆ alkyl, and

wherein the C₁-C₂ alkylene group is optionally substituted with oxo; andR¹⁴ is hydrogen, C₁-C₆ alkyl, 5-10-membered monocyclic or bicyclicheteroaryl or C₆-C₁₀ monocyclic or bicyclic aryl, wherein each C₁-C₆alkyl, aryl or heteroaryl is optionally independently substituted with1, 2, or 3 R⁶;or a pharmaceutically acceptable salt thereof.

In some embodiments, provided herein is a compound of Formula AA

whereinm=0, 1, or 2;n=0, 1, or 2;o=1 or 2;p=0, 1, 2, or 3;whereinA is a 5- to 10-membered monocyclic or bicyclic heteroaryl or a C₆-C₁₀monocyclic or bicyclic aryl;B is a 5- to 10-membered monocyclic or bicyclic heteroaryl or a C₆-C₁₀monocyclic or bicyclic aryl;whereinat least one R⁶ is ortho to the bond connecting the B ring to theNR³(CO) group of Formula AA; R¹ and R² are each independently selectedfrom C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halo,CN, NO₂, COC₁-C₆ alkyl, CO—C₆-C₁₀ aryl, CO (5- to 10-memberedheteroaryl), CO₂C₁-C₆ alkyl, CO₂C₃-C₈ cycloalkyl, OCOC₁-C₆ alkyl,OCOC₆-C₁₀ aryl, OCO (5- to 10-membered heteroaryl), OCO (3- to7-membered heterocycloalkyl), C₆-C₁₀ aryl, 5- to 10-membered heteroaryl,NH₂, NHC₁-C₆ alkyl, N(C₁-C₆ alkyl)₂, NHCOC₁-C₆ alkyl, NHCOC₆-C₁₀ aryl,NHCO (5- to 10-membered heteroaryl), NHCO (3- to 7-memberedheterocycloalkyl), NHCOC₂-C₆ alkynyl, NHCOOCC₁-C₆ alkyl,NH—(C═NR¹³)NR¹¹R¹², CONR⁸R⁹, SF₅, SC₁-C₆ alkyl, S(O₂)C₁-C₆ alkyl,S(O₂)NR¹¹R¹², S(O)C₁-C₆ alkyl, C₃-C₇ cycloalkyl and 3- to 7-memberedheterocycloalkyl,wherein the C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₇ cycloalkyl and 3- to7-membered heterocycloalkyl is optionally substituted with one or moresubstituents each independently selected from hydroxy, halo, CN, oxo,C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰ COOC₁-C₆ alkyl, CONR⁸R⁹, 3- to7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl,OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO (5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC₁-C₆ alkyl, NHCOC₆-C₁₀ aryl,NHCO (5- to 10-membered heteroaryl), NHCO (3- to 7-memberedheterocycloalkyl), and NHCOC₂-C₆ alkynyl;

-   -   wherein each C₁-C₆ alkyl substituent and each C₁-C₆ alkoxy        substituent of the R¹ or R² C₃-C₇ cycloalkyl or of the R¹ or R²        3- to 7-membered heterocycloalkyl is further optionally        independently substituted with one to three hydroxy, halo,        NR⁸R⁹, or oxo;    -   wherein the 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5-        to 10-membered heteroaryl, NHCOC₆-C₁₀ aryl, NHCO (5- to        10-membered heteroaryl) and NHCO (3- to 7-membered        heterocycloalkyl) are optionally substituted with one or more        substituents independently selected from halo, C₁-C₆ alkyl, and        OC₁-C₆ alkyl;        or at least one pair of R¹ and R² on adjacent atoms, taken        together with the atoms connecting them, independently form at        least one C₄-C₈ carbocyclic ring or at least one 5-        to-8-membered heterocyclic ring containing 1 or 2 heteroatoms        independently selected from O, N, and S, wherein the carbocyclic        ring or heterocyclic ring is optionally independently        substituted with one or more substituents independently selected        from hydroxy, halo, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹,        ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹, wherein the        C₁-C₆ alkyl and C₁-C₆ alkoxy are optionally substituted with        hydroxy, halo, oxo, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl,        and CONR⁸R⁹;        R⁶ and R⁷ are each independently selected from C₁-C₆ alkyl,        C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halo, CN, NO₂,        COC₁-C₆ alkyl, CO₂C₁-C₆ alkyl, CO₂C₃-C₈ cycloalkyl, OCOC₁-C₆        alkyl, OCOC₆-C₁₀ aryl, OCO (5- to 10-membered heteroaryl), OCO        (3- to 7-membered heterocycloalkyl), C₆-C₁₀ aryl, 5- to        10-membered heteroaryl, NH₂, NHC₁-C₆ alkyl, N(C₁-C₆ alkyl)₂,        CONR⁸R⁹, SF₅, SC₁-C₆ alkyl, S(O₂)C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl        and 3- to 10-membered heterocycloalkyl, and C₂-C₆ alkenyl,        wherein R⁶ and R⁷ are each optionally substituted with one or        more substituents independently selected from hydroxy, halo, CN,        oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl,        CONR⁸R⁹, 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to        10-membered heteroaryl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO (5-        to 10-membered heteroaryl), OCO (3- to 7-membered        heterocycloalkyl), NHCOC₁-C₆ alkyl, NHCOC₆-C₁₀ aryl, NHCO (5- to        10-membered heteroaryl), NHCO (3- to 7-membered        heterocycloalkyl), NHCOC₂-C₆ alkynyl, C₆-C₁₀ aryloxy, and        S(O₂)C₁-C₆ alkyl; and wherein the C₁-C₆ alkyl or C₁-C₆ alkoxy        that R⁶ or R⁷ is substituted with is optionally substituted with        one or more hydroxyl, C₆-C₁₀ aryl or NR⁸R⁹, or wherein R⁶ or R⁷        is optionally fused to a five- to -seven-membered carbocyclic        ring or heterocyclic ring containing one or two heteroatoms        independently selected from oxygen, sulfur and nitrogen;    -   wherein the 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5-        to 10-membered heteroaryl, NHCOC₆-C₁₀ aryl, NHCO (5- to        10-membered heteroaryl) and NHCO (3- to 7-membered        heterocycloalkyl) are optionally substituted with one or more        substituents independently selected from halo, C₁-C₆ alkyl, and        OC₁-C₆ alkyl;        or at least one pair of R⁶ and R⁷ on adjacent atoms, taken        together with the atoms connecting them, independently form at        least one C₄-C₈ carbocyclic ring or at least one 5- to        8-membered heterocyclic ring containing 1 or 2 heteroatoms        independently selected from O, N, and S, wherein the carbocyclic        ring or heterocyclic ring is optionally independently        substituted with one or more substituents independently selected        from hydroxy, hydroxymethyl, halo, oxo, C₁-C₆ alkyl, C₁-C₆        alkoxy, NR⁸R⁹, CH₂NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and        CONR⁸R⁹;        R¹⁰ is C₁-C₆ alkyl;        each of R⁸ and R⁹ at each occurrence is independently selected        from hydrogen, C₁-C₆ alkyl, (C═NR¹³)NR¹¹R¹², S(O₂)C₁-C₆ alkyl,        S(O₂)NR¹¹R¹², COR¹³, CO₂R¹³ and CONR¹¹R¹²; wherein the C₁-C₆        alkyl is optionally substituted with one or more hydroxy, halo,        C₁-C₆ alkoxy, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₇        cycloalkyl or 3- to 7-membered heterocycloalkyl; or R⁸ and R⁹        taken together with the nitrogen they are attached to form a 3-        to 7-membered ring optionally containing one or more heteroatoms        in addition to the nitrogen they are attached to;        R¹³ is C₁-C₆ alkyl, C₆-C₁₀ aryl, or 5- to 10-membered        heteroaryl;        each of R¹¹ and R¹² at each occurrence is independently selected        from hydrogen and C₁-C₆ alkyl; and        R³ is selected from hydrogen, cyano, hydroxy, C₁-C₆ alkoxy,        C₁-C₆ alkyl, and

wherein the C₁-C₂ alkylene group is optionally substituted with oxo;R¹⁴ is hydrogen, C₁-C₆ alkyl, 5- to 10-membered monocyclic or bicyclicheteroaryl or C₆-C₁₀ monocyclic or bicyclic aryl, wherein each C₁-C₆alkyl, aryl or heteroaryl is optionally independently substituted with 1or 2 R⁶;or a pharmaceutically acceptable salt thereof.

In some embodiments, provided herein is a compound of Formula AA

whereinm=0, 1, or 2;n=0, 1, or 2;o=1 or 2;p=0, 1, 2, or 3,whereinA is a 5- to 10-membered monocyclic or bicyclic heteroaryl or a C₆-C₁₀monocyclic or bicyclic aryl;B is a 5- to 10-membered monocyclic or bicyclic heteroaryl or a C₆-C₁₀monocyclic or bicyclic aryl;whereinat least one R⁶ is ortho to the bond connecting the B ring to the NH(CO)group of Formula AA;R¹ and R² are each independently selected from C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halo, CN, NO₂, COC₁-C₆ alkyl,CO—C₆-C₁₀ aryl; CO (5- to 10-membered heteroaryl); CO₂C₁-C₆ alkyl,CO₂C₃-C₈ cycloalkyl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO (5- to10-membered heteroaryl), OCO (3- to 7-membered heterocycloalkyl), C₆-C₁₀aryl, 5- to 10-membered heteroaryl, NH₂, NHC₁-C₆ alkyl, N(C₁-C₆ alkyl)₂,NHCOC₁-C₆ alkyl, NHCOC₆-C₁₀ aryl, NHCO (5- to 10-membered heteroaryl),NHCO (3- to 7-membered heterocycloalkyl), NHCOC₂-C₆ alkynyl, NHCOOCC₁-C₆alkyl, NH—(C═NR¹³)NR¹¹R¹², CONR⁸R⁹, SF₅, SC₁-C₆ alkyl, S(O₂)C₁-C₆ alkyl,S(O)C₁-C₆ alkyl, S(O₂)NR¹¹R¹², C₃-C₇ cycloalkyl and 3- to 7-memberedheterocycloalkyl,wherein the C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₇ cycloalkyl and 3- to7-membered heterocycloalkyl is optionally substituted with one or moresubstituents each independently selected from hydroxy, halo, CN, oxo,C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, CONR⁸R⁹, 3- to7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl,OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO (5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC₁-C₆ alkyl, NHCOC₆-C₁₀ aryl,NHCO (5- to 10-membered heteroaryl), NHCO (3- to 7-memberedheterocycloalkyl), and NHCOC₂-C₆ alkynyl;

-   -   wherein each C₁-C₆ alkyl substituent and each C₁-C₆ alkoxy        substituent of the R¹ or R² C₃-C₇ cycloalkyl or of the R¹ or R²        3- to 7-membered heterocycloalkyl is further optionally        independently substituted with one to three hydroxy, halo,        NR⁸R⁹, or oxo;    -   wherein the 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5-        to 10-membered heteroaryl, NHCOC₆-C₁₀ aryl, NHCO (5- to        10-membered heteroaryl) and NHCO (3- to 7-membered        heterocycloalkyl) are optionally substituted with one or more        substituents independently selected from halo, C₁-C₆ alkyl, and        OC₁-C₆ alkyl;        or at least one pair of R¹ and R² on adjacent atoms, taken        together with the atoms connecting them, independently form at        least one C₄-C₈ carbocyclic ring or at least one 5- to        8-membered heterocyclic ring containing 1 or 2 heteroatoms        independently selected from O, N, and S, wherein the carbocyclic        ring or heterocyclic ring is optionally independently        substituted with one or more substituents independently selected        from hydroxy, halo, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹,        ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹ wherein the        C₁-C₆ alkyl and C₁-C₆ alkoxy are optionally substituted with        hydroxy, halo, oxo, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl,        and CONR⁸R⁹;

R⁶ and R⁷ are each independently selected from C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halo, CN, NO₂, COC₁-C₆ alkyl,CO₂C₁-C₆ alkyl, CO₂C₃-C₈ cycloalkyl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO (3- to 7-membered heterocycloalkyl),C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, NH₂, NHC₁-C₆ alkyl, N(C₁-C₆alkyl)₂, CONR⁸R⁹, SF₅, S(O₂)C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl and 3- to10-membered heterocycloalkyl, and a C₂-C₆ alkenyl,

wherein R⁶ and R⁷ are each optionally substituted with one or moresubstituents independently selected from hydroxy, halo, CN, oxo, C₁-C₆alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, CONR⁸R⁹, 3- to7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl,OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO (5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC₁-C₆ alkyl, NHCOC₆-C₁₀ aryl,NHCO (5- to 10-membered heteroaryl), NHCO (3- to 7-memberedheterocycloalkyl), NHCOC₂-C₆ alkynyl, C₆-C₁₀ aryloxy, and S(O₂)C₁-C₆alkyl; and wherein the C₁-C₆ alkyl or C₁-C₆ alkoxy that R⁶ or R⁷ issubstituted with is optionally substituted with one or more hydroxyl,C₆-C₁₀ aryl or NR⁸R⁹, or wherein R⁶ or R⁷ is optionally fused to a five-to -seven-membered carbocyclic ring or heterocyclic ring containing oneor two heteroatoms independently selected from oxygen, sulfur andnitrogen;

-   -   wherein the 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5-        to 10-membered heteroaryl, NHCOC₆-C₁₀ aryl, NHCO (5- to        10-membered heteroaryl) and NHCO (3- to 7-membered        heterocycloalkyl) are optionally substituted with one or more        substituents independently selected from halo, C₁-C₆ alkyl, and        OC₁-C₆ alkyl;        or at least one pair of R⁶ and R⁷ on adjacent atoms, taken        together with the atoms connecting them, independently form at        least one C₄-C₈ carbocyclic ring or at least one 5- to        8-membered heterocyclic ring containing 1 or 2 heteroatoms        independently selected from O, N, and S, wherein the carbocyclic        ring or heterocyclic ring is optionally independently        substituted with one or more substituents independently selected        from hydroxy, hydroxymethyl, halo, oxo, C₁-C₆ alkyl, C₁-C₆        alkoxy, NR⁸R⁹, CH₂NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and        CONR⁸R⁹;        each of R⁴ and R⁵ is independently selected from hydrogen and        C₁-C₆ alkyl;        R¹⁰ is C₁-C₆ alkyl;        each of R⁸ and R⁹ at each occurrence is independently selected        from hydrogen, C₁-C₆ alkyl, (C═NR¹³)NR¹¹R¹², S(O₂)C₁-C₆ alkyl,        S(O₂)NR¹¹R¹², COR¹³, CO₂R¹³ and CONR¹¹R¹²; wherein the C₁-C₆        alkyl is optionally substituted with one or more hydroxy, halo,        C₁-C₆ alkoxy, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₇        cycloalkyl or 3- to 7-membered heterocycloalkyl; or        R⁸ and R⁹ taken together with the nitrogen they are attached to        form a 3- to 7-membered ring optionally containing one or more        heteroatoms in addition to the nitrogen they are attached to;        R¹³ is C₁-C₆ alkyl, C₆-C₁₀ aryl, or 5- to 10-membered        heteroaryl;        each of R¹¹ and R¹² at each occurrence is independently selected        from hydrogen and C₁-C₆ alkyl;        R³ is selected from hydrogen, cyano, hydroxy, C₁-C₆ alkoxy,        C₁-C₆ alkyl, and

wherein the C₁-C₂ alkylene group is optionally substituted by oxo;R¹⁴ is hydrogen, C₁-C₆ alkyl, 5- to 10-membered monocyclic or bicyclicheteroaryl or C₆-C₁₀ monocyclic or bicyclic aryl, wherein each C₁-C₆alkyl, aryl or heteroaryl is optionally independently substituted with 1or 2 R⁶;with the proviso that the compound of Formula AA is not a compoundselected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

In some embodiments, provided herein is a compound of Formula AA

whereinm=0, 1, or 2;n=0, 1, or 2;o=1 or 2;p=0, 1, 2, or 3,whereinA is a 5- to 10-membered monocyclic or bicyclic heteroaryl or a C₆-C₁₀monocyclic or bicyclic aryl;B is a 5-membered heteroaryl, a 7-10 membered monocyclic or bicyclicheteroaryl, or a C₆-C₁₀ monocyclic or bicyclic aryl;whereinat least one R⁶ is ortho to the bond connecting the B ring to the NH(CO)group of Formula AA;R¹ and R² are each independently selected from C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halo, CN, NO₂, COC₁-C₆ alkyl,CO—C₆-C₁₀ aryl; CO (5- to 10-membered heteroaryl); CO₂C₁-C₆ alkyl,CO₂C₃-C₈ cycloalkyl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO (5- to10-membered heteroaryl), OCO (3- to 7-membered heterocycloalkyl), C₆-C₁₀aryl, 5- to 10-membered heteroaryl, NH₂, NHC₁-C₆ alkyl, N(C₁-C₆ alkyl)₂,NHCOC₁-C₆ alkyl, NHCOC₆-C₁₀ aryl, NHCO (5- to 10-membered heteroaryl),NHCO (3- to 7-membered heterocycloalkyl), NHCOC₂-C₆ alkynyl, NHCOOCC₁-C₆alkyl, NH—(C═NR¹³)NR¹¹R¹², CONR⁸R⁹, SF₅, SC₁-C₆ alkyl, S(O₂)C₁-C₆ alkyl,S(O)C₁-C₆ alkyl, S(O₂)NR¹¹R¹², C₃-C₇ cycloalkyl and 3- to 7-memberedheterocycloalkyl,wherein the C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₇ cycloalkyl and 3- to7-membered heterocycloalkyl is optionally substituted with one or moresubstituents each independently selected from hydroxy, halo, CN, oxo,C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰ COOC₁-C₆ alkyl, CONR⁸R⁹, 3- to7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl,OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO (5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC₁-C₆ alkyl, NHCOC₆-C₁₀ aryl,NHCO (5- to 10-membered heteroaryl), NHCO (3- to 7-memberedheterocycloalkyl), and NHCOC₂-C₆ alkynyl;

-   -   wherein each C₁-C₆ alkyl substituent and each C₁-C₆ alkoxy        substituent of the R¹ or R² C₃-C₇ cycloalkyl or of the R¹ or R²        3- to 7-membered heterocycloalkyl is further optionally        independently substituted with one to three hydroxy, halo,        NR⁸R⁹, or oxo;    -   wherein the 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5-        to 10-membered heteroaryl, NHCOC₆-C₁₀ aryl, NHCO (5- to        10-membered heteroaryl) and NHCO (3- to 7-membered        heterocycloalkyl) are optionally substituted with one or more        substituents independently selected from halo, C₁-C₆ alkyl, and        OC₁-C₆ alkyl;        or at least one pair of R¹ and R² on adjacent atoms, taken        together with the atoms connecting them, independently form at        least one C₄-C₈ carbocyclic ring or at least one 5- to        8-membered heterocyclic ring containing 1 or 2 heteroatoms        independently selected from O, N, and S, wherein the carbocyclic        ring or heterocyclic ring is optionally independently        substituted with one or more substituents independently selected        from hydroxy, halo, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹,        ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹ wherein the        C₁-C₆ alkyl and C₁-C₆ alkoxy are optionally substituted with        hydroxy, halo, oxo, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl,        and CONR⁸R⁹;        R⁶ and R⁷ are each independently selected from C₁-C₆ alkyl,        C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halo, CN, NO₂,        COC₁-C₆ alkyl, CO₂C₁-C₆ alkyl, CO₂C₃-C₈ cycloalkyl, OCOC₁-C₆        alkyl, OCOC₆-C₁₀ aryl, OCO (5- to 10-membered heteroaryl), OCO        (3- to 7-membered heterocycloalkyl), C₆-C₁₀ aryl, 5- to        10-membered heteroaryl, NH₂, NHC₁-C₆ alkyl, N(C₁-C₆ alkyl)₂,        CONR⁸R⁹, SF₅, S(O₂)C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl and 3- to        10-membered heterocycloalkyl, and a C₂-C₆ alkenyl,        wherein R⁶ and R⁷ are each optionally substituted with one or        more substituents independently selected from hydroxy, halo, CN,        oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl,        CONR⁸R⁹, 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to        10-membered heteroaryl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO (5-        to 10-membered heteroaryl), OCO (3- to 7-membered        heterocycloalkyl), NHCOC₁-C₆ alkyl, NHCOC₆-C₁₀ aryl, NHCO (5- to        10-membered heteroaryl), NHCO (3- to 7-membered        heterocycloalkyl), NHCOC₂-C₆ alkynyl, C₆-C₁₀ aryloxy, and        S(O₂)C₁-C₆ alkyl; and wherein the C₁-C₆ alkyl or C₁-C₆ alkoxy        that R⁶ or R⁷ is substituted with is optionally substituted with        one or more hydroxyl, C₆-C₁₀ aryl or NR⁸R⁹, or wherein R⁶ or R⁷        is optionally fused to a five- to -seven-membered carbocyclic        ring or heterocyclic ring containing one or two heteroatoms        independently selected from oxygen, sulfur and nitrogen;    -   wherein the 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5-        to 10-membered heteroaryl, NHCOC₆-C₁₀ aryl, NHCO (5- to        10-membered heteroaryl) and NHCO (3- to 7-membered        heterocycloalkyl) are optionally substituted with one or more        substituents independently selected from halo, C₁-C₆ alkyl, and        OC₁-C₆ alkyl;        or at least one pair of R⁶ and R⁷ on adjacent atoms, taken        together with the atoms connecting them, independently form at        least one C₄-C₈ carbocyclic ring or at least one 5- to        8-membered heterocyclic ring containing 1 or 2 heteroatoms        independently selected from O, N, and S, wherein the carbocyclic        ring or heterocyclic ring is optionally independently        substituted with one or more substituents independently selected        from hydroxy, hydroxymethyl, halo, oxo, C₁-C₆ alkyl, C₁-C₆        alkoxy, NR⁸R⁹, CH₂NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and        CONR⁸R⁹;        each of R⁴ and R⁵ is independently selected from hydrogen and        C₁-C₆ alkyl;        R¹⁰ is C₁-C₆ alkyl;        each of R⁸ and R⁹ at each occurrence is independently selected        from hydrogen, C₁-C₆ alkyl, (C═NR¹³)NR¹¹R¹², S(O₂)C₁-C₆ alkyl,        S(O₂)NR¹¹R¹², COR¹³, CO₂R¹³ and CONR¹¹R¹²; wherein the C₁-C₆        alkyl is optionally substituted with one or more hydroxy, halo,        C₁-C₆ alkoxy, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₇        cycloalkyl or 3- to 7-membered heterocycloalkyl; or        R⁸ and R⁹ taken together with the nitrogen they are attached to        form a 3- to 7-membered ring optionally containing one or more        heteroatoms in addition to the nitrogen they are attached to;        R¹³ is C₁-C₆ alkyl, C₆-C₁₀ aryl, or 5- to 10-membered        heteroaryl;        each of R¹¹ and R¹² at each occurrence is independently selected        from hydrogen and C₁-C₆ alkyl;        R³ is selected from hydrogen, cyano, hydroxy, C₁-C₆ alkoxy,        C₁-C₆ alkyl, and

wherein the C₁-C₂ alkylene group is optionally substituted by oxo; andR¹⁴ is hydrogen, C₁-C₆ alkyl, 5- to 10-membered monocyclic or bicyclicheteroaryl or C₆-C₁₀ monocyclic or bicyclic aryl, wherein each C₁-C₆alkyl, aryl or heteroaryl is optionally independently substituted with 1or 2 R⁶;or a pharmaceutically acceptable salt thereof.

In some embodiments the variables shown in the formulae herein are asfollows:

The Variables m and n

In some embodiments m=0, 1, or 2.

In some embodiments m=0 or 1.

In some embodiments m=1 or 2.

In some embodiments m=0 or 2.

In some embodiments m=0.

In some embodiments m=1.

In some embodiments m=2.

In some embodiments n=0, 1, or 2.

In some embodiments n=0 or 1.

In some embodiments n=1 or 2.

In some embodiments n=0 or 2.

In some embodiments n=0.

In some embodiments n=1.

In some embodiments n=2.

In some embodiments, m=0 and n=0.

In some embodiments, m=1 and n=0.

In some embodiments, m=1 and n=1.

The Ring a and Substitutions on the Ring A

In some embodiments, A is a 5- to 10-membered (e.g., 5- to 6-membered)monocyclic or bicyclic heteroaryl or a C₆-C₁₀ (e.g., C₆) monocyclic orbicyclic aryl, such as phenyl.

In some embodiments, A is a 5- to 10-membered (e.g., 5- to 6-membered)monocyclic or bicyclic heteroaryl.

In some embodiments, A is a 5-membered heteroaryl containing a sulfurand optionally one or more nitrogens.

In some embodiments, A is a C₆-C₁₀ monocyclic or bicyclic aryl.

In some embodiments, A is phenyl optionally substituted with 1 or 2 R¹and optionally substituted with 1 or 2 R².

In some embodiments, A is naphthyl optionally substituted with 1 or 2 R¹and optionally substituted with 1 or 2 R².

In some embodiments, A is furanyl optionally substituted with 1 or 2 R¹and optionally substituted with 1 R².

In some embodiments, A is furanyl optionally substituted with 1 R¹ andoptionally substituted with 1 or 2 R².

In some embodiments, A is thiophenyl optionally substituted with 1 or 2R¹ and optionally substituted with 1 or 2 R².

In some embodiments, A is oxazolyl optionally substituted with 1 or 2 R¹and optionally substituted with 1 or 2 R².

In some embodiments, A is thiazolyl optionally substituted with 1 or 2R¹ and optionally substituted with 1 or 2 R².

In some embodiments, A is oxazolyl optionally substituted with 2 R¹ oroptionally substituted with 2 R².

In some embodiments, A is thiazolyl optionally substituted with 2 R¹ oroptionally substituted with 2 R².

In some embodiments, A is pyrazolyl optionally substituted with 1 or 2R¹ and optionally substituted with 1 or 2 R².

In some embodiments, A is pyrazolyl optionally substituted with 1 R¹ andoptionally substituted with 1 or 2 R².

In some embodiments, A is pyrazolyl optionally substituted with 1 or 2R¹ and optionally substituted with 1 R².

In some embodiments, A is pyridyl optionally substituted with 1 or 2 R¹and optionally substituted with 1 or 2 R².

In some embodiments, A is indazolyl optionally substituted with 1 or 2R¹ and optionally substituted with 1 or 2 R².

In some embodiments, A is phenyl substituted with 1 R¹ and optionallysubstituted with 1 R².

In some embodiments, A is naphthyl substituted with 1 R¹ and optionallysubstituted with 1 R². In some embodiments, A is furanyl substitutedwith 1 R¹ and optionally substituted with 1 R². In some embodiments, Ais thiophenyl substituted with 1 R¹ and optionally substituted with 1R².

In some embodiments, A is oxazolyl substituted with 1 R¹ and optionallysubstituted with 1 R².

In some embodiments, A is thiazolyl substituted with 1 R¹ and optionallysubstituted with 1 R².

In some embodiments, A is pyrazolyl substituted with 1 R¹ and optionallysubstituted with 1 R².

In some embodiments, A is pyridyl substituted with 1 R¹ and optionallysubstituted with 1 R².

In some embodiments, A is indazolyl optionally substituted with 1 R¹ andoptionally substituted with 1 R².

In some embodiments, A is phenyl substituted with 1 R¹ and substitutedwith 1 R².

In some embodiments, A is furanyl substituted with 1 R¹ and substitutedwith 1 R².

In some embodiments, A is thiophenyl substituted with 1 R¹ andsubstituted with 1 R².

In some embodiments, A is oxazolyl substituted with 1 R¹ and substitutedwith 1 R².

In some embodiments, A is thiazolyl substituted with 1 R¹ andsubstituted with 1 R².

In some embodiments, A is pyrazolyl substituted with 1 R¹ andsubstituted with 1 R².

In some embodiments, A is pyridyl substituted with 1 R¹ and substitutedwith 1 R².

In some embodiments, A is phenyl, m is 0 or 1, and n is 0, 1, or 2.

In some embodiments, A is furanyl, m is 0 or 1, and n is 0, 1, or 2.

In some embodiments, A is thiophenyl, m is 0 or 1, and n is 0, 1, or 2.

In some embodiments, A is oxazolyl, m is 0 or 1, and n is 0, 1, or 2.

In some embodiments, A is thiazolyl, m is 0 or 1, and n is 0, 1, or 2.

In some embodiments, A is pyrazolyl, m is 0 or 1, and n is 0, 1, or 2.

In some embodiments, A is pyridyl, m is 0 or 1, and n is 0, 1, or 2.

In some embodiments, A is indazolyl, m is 0 or 1, and n is 0, 1, or 2.

In some embodiments, A is phenyl, m is 0, and n is 0 or 1.

In some embodiments, A is furanyl, m is 0, and n is 0 or 1.

In some embodiments, A is thiophenyl, m is 0, and n is 0 or 1.

In some embodiments, A is oxazolyl, m is 0, and n is 0 or 1.

In some embodiments, A is thiazolyl, m is 0, and n is 0 or 1.

In some embodiments, A is pyrazolyl, m is 0, and n is 0 or 1.

In some embodiments, A is pyridyl, m is 0, and n is 0 or 1.

In some embodiments, A is one of the rings disclosed hereinbelowoptionally substituted as disclosed hereinbelow, wherein in each casethe bond that is shown as being broken by the wavy line

connects A to the S(O)(NR³R³)═N moiety of Formula AA.

In some embodiments, the optionally substituted ring A

In some embodiments, the optionally substituted ring A is

In some embodiments, the optionally substituted ring A is

In some embodiments, the optionally substituted ring A is

In some embodiments, the optionally substituted ring A is

In some embodiments, the optionally substituted ring A is

In some embodiments, the optionally substituted ring A is

In some embodiments, the optionally substituted ring A is

In some embodiments, the optionally substituted ring A is

In some embodiments, the optionally substituted ring A is

In some embodiments, the optionally substituted ring A is

In some embodiments, the optionally substituted ring A is

In some embodiments, the optionally substituted ring A is

In some embodiments, the optionally substituted ring A is

In some embodiments, the optionally substituted ring A is

In some embodiments, the optionally substituted ring A is

In some embodiments, the optionally substituted ring A is

In some embodiments, the optionally substituted ring A is

In some embodiments, the optionally substituted ring A is

In some embodiments, the optionally substituted ring A is

In some embodiments, the optionally substituted ring A is

In some embodiments, the optionally substituted ring A is

In some embodiments, the optionally substituted ring A is

In some embodiments, the optionally substituted ring A is

In some embodiments, the optionally substituted ring A is

In some embodiments, the optionally substituted ring A is

In some embodiments, the optionally substituted ring A is

In some embodiments, the optionally substituted ring A is

In some embodiments, the optionally substituted ring A is

In some embodiments, the optionally substituted ring A is

In some embodiments, the optionally substituted ring A is

In some embodiments, the optionally substituted ring A is

In some embodiments, the optionally substituted ring A is

In some embodiments, the optionally substituted ring A is

In some embodiments, the optionally substituted ring A is

In some embodiments, the optionally substituted ring A is

In some embodiments, the optionally substituted ring A is

In some embodiments, the optionally substituted ring A is

In some embodiments, the optionally substituted ring A is

In some embodiments, the optionally substituted ring A is

In some embodiments, the optionally substituted ring A is

In some embodiments, the optionally substituted ring A is

In some embodiments, the optionally substituted ring A is

In some embodiments, the optionally substituted ring A is

In some embodiments, the optionally substituted ring A is

In some embodiments, the optionally substituted ring A is

In some embodiments, the optionally substituted ring A is

In some embodiments, the optionally substituted ring A is

In some embodiments, the optionally substituted ring A is

In some embodiments, the optionally substituted ring A is

In some embodiments, the optionally substituted ring A is

In some embodiments, the optionally substituted ring A is

In some embodiments, the optionally substituted ring A is

In some embodiments, the optionally substituted ring A is

In some embodiments, the optionally substituted ring A is

In some embodiments, the optionally substituted ring A is

In some embodiments, the optionally substituted ring A is

In some embodiments, the optionally substituted ring A is

In some embodiments, the optionally substituted ring A is

In some embodiments, the optionally substituted ring A is

In some embodiments, the optionally substituted ring A is

In some embodiments, the optionally substituted ring A is

In some embodiments, the optionally substituted ring A is

In some embodiments, the optionally substituted ring A is

In some embodiments, the optionally substituted ring A is

In some embodiments, the optionally substituted ring A is

In some embodiments, the optionally substituted ring A is

In some embodiments, the optionally substituted ring A is

In some embodiments, the optionally substituted ring A is

In some embodiments, the optionally substituted ring A is

In some embodiments, the optionally substituted ring A is

In some embodiments, the optionally substituted ring A is

In some embodiments, the optionally substituted ring A is

In some embodiments, the optionally substituted ring A is

In some embodiments, the optionally substituted ring A is

In some embodiments, the optionally substituted ring A is

In some embodiments, the optionally substituted ring A is

In some embodiments, the optionally substituted ring A is

In some embodiments, the optionally substituted ring A is

In some embodiments, the optionally substituted ring A is

In some embodiments, the optionally substituted ring A is

The Groups R¹ and R²

In some embodiments,

R¹ and R² are each independently selected from C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halo, CN, NO₂, COC₁-C₆ alkyl,CO—C₆-C₁₀ aryl, CO (5- to 10-membered heteroaryl), CO₂C₁-C₆ alkyl,CO₂C₃-C₈ cycloalkyl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO (5- to10-membered heteroaryl), OCO (3- to 7-membered heterocycloalkyl), C₆-C₁₀aryl, 5- to 10-membered heteroaryl, NH₂, NHC₁-C₆ alkyl, N(C₁-C₆ alkyl)₂,CONR⁸R⁹, SF₅, SC₁-C₆ alkyl, S(O₂)C₁-C₆ alkyl, S(O₂)NR¹¹R¹², S(O)C₁-C₆alkyl, C₃-C₇ cycloalkyl and 3- to 7-membered heterocycloalkyl,wherein the C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₇ cycloalkyl and 3- to7-membered heterocycloalkyl is optionally substituted with one or moresubstituents each independently selected from hydroxy, halo, CN, oxo,C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰ COOC₁-C₆ alkyl, CONR⁸R⁹, 3- to7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl,OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO (5- to 10-membered heteroaryl), andOCO (3- to 7-membered heterocycloalkyl);

-   -   wherein each C₁-C₆ alkyl substituent and each C₁-C₆ alkoxy        substituent of the R¹ or R² C₃-C₇ cycloalkyl or of the R¹ or R²        3- to 7-membered heterocycloalkyl is further optionally        independently substituted with one to three hydroxy, halo,        NR⁸R⁹, or oxo;    -   wherein the 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, and        5- to 10-membered heteroaryl are optionally substituted with one        or more substituents independently selected from halo, C₁-C₆        alkyl, and OC₁-C₆ alkyl;        or at least one pair of R¹ and R² on adjacent atoms, taken        together with the atoms connecting them, independently form at        least one C₄-C₈ carbocyclic ring or at least one 5-        to-8-membered heterocyclic ring containing 1 or 2 heteroatoms        independently selected from O, N, and S, wherein the carbocyclic        ring or heterocyclic ring is optionally independently        substituted with one or more substituents independently selected        from hydroxy, halo, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹,        ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹;

In some embodiments,

R¹ and R² are each independently selected from C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halo, CN, NO₂, COC₁-C₆ alkyl,CO—C₆-C₁₀ aryl; CO (5- to 10-membered heteroaryl); CO₂C₁-C₆ alkyl,CO₂C₃-C₈ cycloalkyl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO (5- to10-membered heteroaryl), OCO (3- to 7-membered heterocycloalkyl), C₆-C₁₀aryl, 5- to 10-membered heteroaryl, NH₂, NHC₁-C₆ alkyl, N(C₁-C₆ alkyl)₂,CONR⁸R⁹, SF₅, SC₁-C₆ alkyl, S(O₂)C₁-C₆ alkyl, S(O₂)NR¹¹R¹², S(O)C₁-C₆alkyl, C₃-C₇ cycloalkyl and 3- to 7-membered heterocycloalkyl,wherein the C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₇ cycloalkyl and 3- to7-membered heterocycloalkyl is optionally substituted with one or moresubstituents each independently selected from hydroxy, halo, CN, oxo,C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, CONR⁸R⁹, 3- to7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl,OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO (5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC₁-C₆ alkyl, NHCOC₆-C₁₀ aryl,NHCO (5- to 10-membered heteroaryl), NHCO (3- to 7-memberedheterocycloalkyl), and NHCOC₂-C₆ alkynyl;

-   -   wherein each C₁-C₆ alkyl substituent and each C₁-C₆ alkoxy        substituent of the R¹ or R² C₃-C₇ cycloalkyl or of the R¹ or R²        3- to 7-membered heterocycloalkyl is further optionally        independently substituted with one to three hydroxy, halo,        NR⁸R⁹, or oxo;    -   wherein the 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5-        to 10-membered heteroaryl, NHCOC₆-C₁₀ aryl, NHCO (5- to        10-membered heteroaryl) and NHCO (3- to 7-membered        heterocycloalkyl) are optionally substituted with one or more        substituents independently selected from halo, C₁-C₆ alkyl, and        OC₁-C₆ alkyl;        or at least one pair of R¹ and R² on adjacent atoms, taken        together with the atoms connecting them, independently form at        least one C₄-C₈ carbocyclic ring or at least one 5- to        8-membered heterocyclic ring containing 1 or 2 heteroatoms        independently selected from O, N, and S, wherein the carbocyclic        ring or heterocyclic ring is optionally independently        substituted with one or more substituents independently selected        from hydroxy, halo, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹,        ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹;

In some embodiments,

R¹ and R² are each independently selected from C₁-C₆ haloalkyl, C₁-C₆alkoxy, C₁-C₆ haloalkoxy, halo, CN, NO₂, COC₁-C₆ alkyl, CO—C₆-C₁₀ aryl,CO (5- to 10-membered heteroaryl), CO₂C₁-C₆ alkyl, CO₂C₃-C₈ cycloalkyl,OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO (5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C₆-C₁₀ aryl, 5- to 10-memberedheteroaryl, NH₂, NHC₁-C₆ alkyl, N(C₁-C₆ alkyl)₂, CONR⁸R⁹, SF₅, SC₁-C₆alkyl, S(O₂)C₁-C₆ alkyl, S(O₂)NR¹¹R¹², S(O)C₁-C₆ alkyl, C₃-C₇ cycloalkyland 3- to 7-membered heterocycloalkyl,wherein the C₃-C₇ cycloalkyl, C₁-C₆ haloalkyl, and 3- to 7-memberedheterocycloalkyl is optionally substituted with one or more substituentseach independently selected from hydroxy, halo, CN, oxo, C₁-C₆ alkyl,C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, CONR⁸R⁹, 3- to 7-memberedheterocycloalkyl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆alkyl, OCOC₆-C₁₀ aryl, OCO (5- to 10-membered heteroaryl), OCO (3- to7-membered heterocycloalkyl), NHCOC₁-C₆ alkyl, NHCOC₆-C₁₀ aryl, NHCO (5-to 10-membered heteroaryl), NHCO (3- to 7-membered heterocycloalkyl),and NHCOC₂-C₆ alkynyl;

-   -   wherein each C₁-C₆ alkyl substituent and each C₁-C₆ alkoxy        substituent of the R¹ or R² C₃-C₇ cycloalkyl or of the R¹ or R²        3- to 7-membered heterocycloalkyl is further optionally        independently substituted with one to three hydroxy, halo,        NR⁸R⁹, or oxo;    -   wherein the 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5-        to 10-membered heteroaryl, NHCOC₆-C₁₀ aryl, NHCO (5- to        10-membered heteroaryl) and NHCO (3- to 7-membered        heterocycloalkyl) are optionally substituted with one or more        substituents independently selected from halo, C₁-C₆ alkyl, and        OC₁-C₆ alkyl;        or at least one pair of R¹ and R² on adjacent atoms, taken        together with the atoms connecting them, independently form at        least one C₄-C₈ carbocyclic ring or at least one 5- to        8-membered heterocyclic ring containing 1 or 2 heteroatoms        independently selected from O, N, and S, wherein the carbocyclic        ring or heterocyclic ring is optionally independently        substituted with one or more substituents independently selected        from hydroxy, halo, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹,        ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹.

In some embodiments,

R¹ and R² are each independently selected from C₁-C₆ alkyl, halo, CN,NO₂, COC₁-C₆ alkyl, CO—C₆-C₁₀ aryl, CO (5- to 10-membered heteroaryl),CO₂C₁-C₆ alkyl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO (5- to 10-memberedheteroaryl), OCO (3- to 7-membered heterocycloalkyl), C₆-C₁₀ aryl, 5- to10-membered heteroaryl, NH₂, NHC₁-C₆ alkyl, N(C₁-C₆ alkyl)₂, CONR⁸R⁹,SF₅, SC₁-C₆ alkyl, S(O₂)C₁-C₆ alkyl, S(O₂)NR¹¹R¹², S(O)C₁-C₆ alkyl,C₃-C₇ cycloalkyl and 3- to 7-membered heterocycloalkyl,wherein the C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₇ cycloalkyl and 3- to7-membered heterocycloalkyl is optionally substituted with one or moresubstituents each independently selected from hydroxy, halo, CN, oxo,C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, CONR⁸R⁹, 3- to7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl,OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO (5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC₁-C₆ alkyl, NHCOC₆-C₁₀ aryl,NHCO (5- to 10-membered heteroaryl), NHCO (3- to 7-memberedheterocycloalkyl), and NHCOC₂-C₆ alkynyl;

-   -   wherein each C₁-C₆ alkyl substituent and each C₁-C₆ alkoxy        substituent of the R¹ or R² C₃-C₇ cycloalkyl or of the R¹ or R²        3- to 7-membered heterocycloalkyl is further optionally        independently substituted with one to three hydroxy, halo,        NR⁸R⁹, or oxo;    -   wherein the 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5-        to 10-membered heteroaryl, NHCOC₆-C₁₀ aryl, NHCO (5- to        10-membered heteroaryl) and NHCO (3- to 7-membered        heterocycloalkyl) are optionally substituted with one or more        substituents independently selected from halo, C₁-C₆ alkyl, and        OC₁-C₆ alkyl;        or at least one pair of R¹ and R² on adjacent atoms, taken        together with the atoms connecting them, independently form at        least one C₄-C₈ carbocyclic ring or at least one 5- to        8-membered heterocyclic ring containing 1 or 2 heteroatoms        independently selected from O, N, and S, wherein the carbocyclic        ring or heterocyclic ring is optionally independently        substituted with one or more substituents independently selected        from hydroxy, halo, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹,        ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹.

In some embodiments,

R¹ and R² are each independently selected from C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halo, CN, NO₂, COC₁-C₆ alkyl,CO—C₆-C₁₀ aryl, CO (5- to 10-membered heteroaryl), CO₂C₁-C₆ alkyl,CO₂C₃-C₈ cycloalkyl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO (5- to10-membered heteroaryl), OCO (3- to 7-membered heterocycloalkyl), C₆-C₁₀aryl, 5- to 10-membered heteroaryl, NH₂, NHC₁-C₆ alkyl, N(C₁-C₆ alkyl)₂,CONR⁸R⁹, SF₅, SC₁-C₆ alkyl, S(O₂)C₁-C₆ alkyl, S(O₂)NR¹¹R¹², S(O)C₁-C₆alkyl, C₃-C₇ cycloalkyl and 3- to 7-membered heterocycloalkyl,wherein the C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₇ cycloalkyl and 3- to7-membered heterocycloalkyl is optionally substituted with one or moresubstituents each independently selected from hydroxy, halo, CN, oxo,C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, CONR⁸R⁹, 3- to7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl,OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO (5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC₁-C₆ alkyl, NHCOC₆-C₁₀ aryl,NHCO (5- to 10-membered heteroaryl), NHCO (3- to 7-memberedheterocycloalkyl), and NHCOC₂-C₆ alkynyl;

-   -   wherein each C₁-C₆ alkyl substituent and each C₁-C₆ alkoxy        substituent of the R¹ or R² C₃-C₇ cycloalkyl or of the R¹ or R²        3- to 7-membered heterocycloalkyl is further optionally        independently substituted with one to three hydroxy, halo, or        oxo; wherein the 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl,        5- to 10-membered heteroaryl, NHCOC₆-C₁₀ aryl, NHCO (5- to        10-membered heteroaryl) and NHCO (3- to 7-membered        heterocycloalkyl) are optionally substituted with one or more        substituents independently selected from halo, C₁-C₆ alkyl, and        OC₁-C₆ alkyl;        or at least one pair of R¹ and R² on adjacent atoms, taken        together with the atoms connecting them, independently form at        least one C₄-C₈ carbocyclic ring or at least one 5-        to-8-membered heterocyclic ring containing 1 or 2 heteroatoms        independently selected from O, N, and S, wherein the carbocyclic        ring or heterocyclic ring is optionally independently        substituted with one or more substituents independently selected        from hydroxy, halo, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹,        ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹.

In some embodiments,

R¹ and R² are each independently selected from C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halo, CN, NO₂, COC₁-C₆ alkyl,CO—C₆-C₁₀ aryl, CO (5- to 10-membered heteroaryl), CO₂C₁-C₆ alkyl,CO₂C₃-C₈ cycloalkyl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO (5- to10-membered heteroaryl), OCO (3- to 7-membered heterocycloalkyl), C₆-C₁₀aryl, 5- to 10-membered heteroaryl, NH₂, NHC₁-C₆ alkyl, N(C₁-C₆ alkyl)₂,CONR⁸R⁹, SF₅, SC₁-C₆ alkyl, S(O₂)C₁-C₆ alkyl, S(O₂)NR¹¹R¹², S(O)C₁-C₆alkyl, C₃-C₇ cycloalkyl and 3- to 7-membered heterocycloalkyl,wherein the C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₇ cycloalkyl and 3- to7-membered heterocycloalkyl is optionally substituted with one or moresubstituents each independently selected from hydroxy, halo, CN, oxo,C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, CONR⁸R⁹, 3- to7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl,OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO (5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC₁-C₆ alkyl, NHCOC₆-C₁₀ aryl,NHCO (5- to 10-membered heteroaryl), NHCO (3- to 7-memberedheterocycloalkyl), and NHCOC₂-C₆ alkynyl;

-   -   wherein the 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5-        to 10-membered heteroaryl, NHCOC₆-C₁₀ aryl, NHCO (5- to        10-membered heteroaryl) and NHCO (3- to 7-membered        heterocycloalkyl) are optionally substituted with one or more        substituents independently selected from halo, C₁-C₆ alkyl, and        OC₁-C₆ alkyl.

In some embodiments,

R¹ and R² are each independently selected from C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halo, CN, NO₂, COC₁-C₆ alkyl,CO—C₆-C₁₀ aryl, CO (5- to 10-membered heteroaryl), CO₂C₁-C₆ alkyl,CO₂C₃-C₈ cycloalkyl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO (5- to10-membered heteroaryl), OCO (3- to 7-membered heterocycloalkyl), C₆-C₁₀aryl, 5- to 10-membered heteroaryl, NH₂, NHC₁-C₆ alkyl, N(C₁-C₆ alkyl)₂,CONR⁸R⁹, SF₅, SC₁-C₆ alkyl, S(O₂)C₁-C₆ alkyl, S(O₂)NR¹¹R¹², S(O)C₁-C₆alkyl, C₃-C₇ cycloalkyl and 3- to 7-membered heterocycloalkyl,wherein the C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₇ cycloalkyl and 3- to7-membered heterocycloalkyl are each unsubstituted;or at least one pair of R¹ and R² on adjacent atoms, taken together withthe atoms connecting them, independently form at least one C₄-C₈carbocyclic ring or at least one 5- to-8-membered heterocyclic ringcontaining 1 or 2 heteroatoms independently selected from O, N, and S,wherein the carbocyclic ring or heterocyclic ring is optionallyindependently substituted with one or more substituents independentlyselected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹,═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹;

In some embodiments,

R¹ and R² are each independently selected from C₁-C₆ alkyl, halo, CN,COC₁-C₆ alkyl, CO₂C₁-C₆ alkyl, C₆-C₁₀ aryl, S(O)C₁-C₆ alkyl, 5- to10-membered heteroaryl, and 3- to 7-membered heterocycloalkyl,wherein the C₁-C₆ alkyl and 3- to 7-membered heterocycloalkyl isoptionally substituted with one or more substituents each independentlyselected from hydroxy and oxo.

In some embodiments, m=1; n=0; and

R¹ is selected from C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆haloalkoxy, halo, CN, NO₂, COC₁-C₆ alkyl, CO—C₆-C₁₀ aryl, CO (5- to10-membered heteroaryl), CO₂C₁-C₆ alkyl, CO₂C₃-C₈ cycloalkyl, OCOC₁-C₆alkyl, OCOC₆-C₁₀ aryl, OCO (5- to 10-membered heteroaryl), OCO (3- to7-membered heterocycloalkyl), C₆-C₁₀ aryl, 5- to 10-membered heteroaryl,NH₂, NHC₁-C₆ alkyl, N(C₁-C₆ alkyl)₂, CONR⁸R⁹, SF₅, SC₁-C₆ alkyl,S(O₂)C₁-C₆ alkyl, S(O₂)NR¹¹R¹², S(O)C₁-C₆ alkyl, C₃-C₇ cycloalkyl and 3-to 7-membered heterocycloalkyl,wherein the C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₇ cycloalkyl and 3- to7-membered heterocycloalkyl is optionally substituted with one or moresubstituents each independently selected from hydroxy, halo, CN, oxo,C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, CONR⁸R⁹, 3- to7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl,OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO (5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC₁-C₆ alkyl, NHCOC₆-C₁₀ aryl,NHCO (5- to 10-membered heteroaryl), NHCO (3- to 7-memberedheterocycloalkyl), and NHCOC₂-C₆ alkynyl;

-   -   wherein the 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5-        to 10-membered heteroaryl, NHCOC₆-C₁₀ aryl, NHCO (5- to        10-membered heteroaryl) and NHCO (3- to 7-membered        heterocycloalkyl) are optionally substituted with one or more        substituents independently selected from halo, C₁-C₆ alkyl, and        OC₁-C₆ alkyl.

In some embodiments, m=1; n=0; and,

R¹ is selected from C₁-C₆ alkyl, halo, CN, COC₁-C₆ alkyl, CO₂C₁-C₆alkyl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, S(O)C₁-C₆ alkyl, and3- to 7-membered heterocycloalkyl, wherein the C₁-C₆ alkyl and 3- to7-membered heterocycloalkyl is optionally substituted with one or moresubstituents each independently selected from hydroxy and oxo.

In some embodiments, m=1; n=1; and

R¹ and R² are each independently selected from C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halo, CN, NO₂, COC₁-C₆ alkyl,CO—C₆-C₁₀ aryl, CO (5- to 10-membered heteroaryl), CO₂C₁-C₆ alkyl,CO₂C₃-C₈ cycloalkyl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO (5- to10-membered heteroaryl), OCO (3- to 7-membered heterocycloalkyl), C₆-C₁₀aryl, 5- to 10-membered heteroaryl, NH₂, NHC₁-C₆ alkyl, N(C₁-C₆ alkyl)₂,CONR⁸R⁹, SF₅, SC₁-C₆ alkyl, S(O₂)C₁-C₆ alkyl, S(O₂)NR¹¹R¹², S(O)C₁-C₆alkyl, C₃-C₇ cycloalkyl and 3- to 7-membered heterocycloalkyl,wherein the C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₇ cycloalkyl and 3- to7-membered heterocycloalkyl is optionally substituted with one or moresubstituents each independently selected from hydroxy, halo, CN, oxo,C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, CONR⁸R⁹, 3- to7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl,OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO (5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC₁-C₆ alkyl, NHCOC₆-C₁₀ aryl,NHCO (5- to 10-membered heteroaryl), NHCO (3- to 7-memberedheterocycloalkyl), and NHCOC₂-C₆ alkynyl; wherein the 3- to 7-memberedheterocycloalkyl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, NHCOC₆-C₁₀aryl, NHCO (5- to 10-membered heteroaryl) and NHCO (3- to 7-memberedheterocycloalkyl) are optionally substituted with one or moresubstituents independently selected from halo, C₁-C₆ alkyl, and OC₁-C₆alkyl;

In some embodiments, m=1; n=1; and,

R¹ and R² are each independently selected from C₁-C₆ alkyl, halo, CN,COC₁-C₆ alkyl, CO₂C₁-C₆ alkyl, C₆-C₁₀ aryl, 5- to 10-memberedheteroaryl, S(O)C₁-C₆ alkyl, and 3- to 7-membered heterocycloalkyl,wherein the C₁-C₆ alkyl and 3- to 7-membered heterocycloalkyl isoptionally substituted with one or more substituents each independentlyselected from hydroxy and oxo.

In some embodiments, m=1; n=1; and

R¹ and R² are on adjacent atoms, and taken together with the atomsconnecting them, form a C₄-C₈ carbocyclic ring or a 5- to-8-memberedheterocyclic ring containing 1 or 2 heteroatoms independently selectedfrom O, N, and S, wherein the carbocyclic ring or heterocyclic ring isoptionally independently substituted with one or more substituentsindependently selected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₁-C₆alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹.

In some embodiments, m=1; n=1; and

R¹ and R² are on adjacent atoms, and taken together with the atomsconnecting them, form a C₆ carbocyclic ring or a 5-to-6-memberedheterocyclic ring containing 1 or 2 heteroatoms independently selectedfrom O, N, and S, wherein the carbocyclic ring or heterocyclic ring isoptionally independently substituted with one or more substituentsindependently selected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₁-C₆alkoxy, NR⁸R⁹, NR¹⁰ COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹.

In some embodiments, m=1; n=1; and

R¹ and R² are on adjacent atoms, and taken together with the atomsconnecting them, form a C₅ carbocyclic ring or a 5- to-6-memberedheterocyclic ring containing 1 or 2 heteroatoms independently selectedfrom O, N, and S, wherein the carbocyclic ring or heterocyclic ring isoptionally independently substituted with one or more substituentsindependently selected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₁-C₆alkoxy, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹.

In some embodiments, m=1; n=1; and

R¹ and R² are on adjacent atoms, and taken together with the atomsconnecting them, form a C₄-C₈ carbocyclic ring or a 5- to 8-memberedheterocyclic ring containing 1 or 2 heteroatoms independently selectedfrom O, N, and S, wherein the carbocyclic ring or heterocyclic ring isunsubstituted.

Particular embodiments wherein m=1 and n=0:

In some embodiments, R¹ is C₁-C₆ alkyl optionally substituted with oneor more hydroxy.

In some embodiments, R¹ is 1-hydroxy-2-methylpropan-2-yl.

In some embodiments, R¹ is 2-hydroxyethyl.

In some embodiments, R¹ is C₁-C₆ alkyl.

In some embodiments, R¹ is methyl.

In some embodiments, R¹ is isopropyl.

In some embodiments, R¹ is isopropyl.

In some embodiments, R¹ is C₁-C₆ alkyl substituted with hydroxy at thecarbon directly connected to ring A.

In some embodiments, R¹ is 2-hydroxy-2-propyl.

In some embodiments, R¹ is hydroxymethyl.

In some embodiments, R¹ is 1-hydroxyethyl.

In some embodiments, R¹ is 1-hydroxy-2-propyl.

In some embodiments, R¹ is C₁-C₆ alkyl substituted with two or morehydroxy groups.

In some embodiments, R¹ is C₁-C₆ alkyl substituted with two or morehydroxy groups, wherein one of the two or more hydroxy groups is bondedto the carbon directly connected to ring A.

In some embodiments, R¹ is 1,2-dihydroxy-prop-2-yl.

In some embodiments, R¹ is C₃-C₇ cycloalkyl optionally substituted withone or more hydroxy.

In some embodiments, R¹ is C₃-C₇ cycloalkyl.

In some embodiments, R¹ is C₃-C₇ cycloalkyl substituted with hydroxy atthe carbon directly connected to ring A.

In some embodiments, R¹ is 1-hydroxy-1-cyclopropyl.

In some embodiments, R¹ is 1-hydroxy-1-cyclobutyl.

In some embodiments, R¹ is 1-hydroxy-1-cyclopentyl.

In some embodiments, R¹ is 1-hydroxy-1-cyclohexyl.

In some embodiments, R¹ is 3- to 7-membered heterocycloalkyl optionallysubstituted with one or more hydroxy.

In some embodiments, R¹ is 3- to 7-membered heterocycloalkyl.

In some embodiments, R¹ is morpholinyl (e.g., 1-morpholinyl).

In some embodiments, R¹ is 1,3-dioxolan-2-yl.

In some embodiments, R¹ is 3- to 7-membered heterocycloalkyl optionallysubstituted with one or more C₁-C₆ alkyl.

In some embodiments, R¹ is 1-methylpyrrolidin-2-yl.

In some embodiments, R¹ is 3- to 7-membered heterocycloalkyl substitutedwith hydroxy at the carbon directly connected to ring A.

In some embodiments, R¹ is C₁-C₆ alkyl optionally substituted with oneor more oxo.

In some embodiments, R¹ is COCH₃.

In some embodiments, R¹ is COCH₂CH₃.

In some embodiments, R¹ is C₃-C₇ cycloalkyl optionally substituted withone or more oxo.

In some embodiments, R¹ is 3- to 7-membered heterocycloalkyl optionallysubstituted with one or more oxo.

In some embodiments, R¹ is C₁-C₆ alkyl optionally substituted with oneor more C₁-C₆ alkoxy.

In some embodiments, R¹ is 2-methoxy-2-propyl.

In some embodiments, R¹ is methoxymethyl.

In some embodiments, R¹ is C₃-C₇ cycloalkyl optionally substituted withone or more C₁-C₆ alkoxy.

In some embodiments, R¹ is 3- to 7-membered heterocycloalkyl optionallysubstituted with one or more C₁-C₆ alkoxy.

In some embodiments, R¹ is C₁-C₆ alkyl optionally substituted with oneor more NR⁸R⁹.

In some embodiments, R¹ is C₁-C₆ alkyl substituted with NR⁸R⁹ at thecarbon directly connected to ring A.

In some embodiments, R¹ is (methylamino)methyl.

In some embodiments, R¹ is (dimethylamino)methyl.

In some embodiments, R¹ is aminomethyl.

In some embodiments, R¹ is N-methylacetamidomethyl.

In some embodiments, R¹ is 1-(dimethylamino)eth-1-yl.

In some embodiments, R¹ is 2-(dimethylamino)prop-2-yl.

In some embodiments, R¹ is (2-methoxy-eth-1-yl)(methyl)aminomethyl.

In some embodiments, R¹ is (methyl)(acetyl)aminomethyl.

In some embodiments, R¹ is (methyl)(cyclopropylmethyl)aminomethyl.

In some embodiments, R¹ is (methyl)(2,2-difluoroeth-1-yl)aminomethyl.

In some embodiments, R¹ is C₃-C₇ cycloalkyl optionally substituted withone or more NR⁸R⁹.

In some embodiments, R¹ is 3- to 7-membered heterocycloalkyl optionallysubstituted with one or more NR⁸R⁹.

In some embodiments, R¹ is C₁-C₆ haloalkyl optionally substituted withone or more hydroxy.

In some embodiments, R¹ is C₁-C₆ alkoxy.

In some embodiments, R¹ is C₁-C₆ haloalkoxy.

In some embodiments, R¹ is C₁-C₆ alkyl optionally substituted with 3- to7-membered heterocycloalkyl, wherein the 3- to 7-memberedheterocycloalkyl is further optionally substituted as defined elsewhereherein.

In some embodiments, R¹ is pyrrolidinylmethyl (e.g.,pyrrolidin-1-ylmethyl).

In some embodiments, R¹ is optionally substituted pyrrolidinylmethyl(e.g., 3,3-difluoropyrrolidin-1-ylmethyl).

In some embodiments, R¹ is azetidinylmethyl (e.g., azetidin-1-ylmethyl).

In some embodiments, R¹ is optionally substituted azetidinylmethyl(e.g., 3-methoxyazetidin-1-ylmethyl).

In some embodiments, R¹ is morpholinylmethyl (e.g.,morpholin-4-ylmethyl).

In some embodiments, R¹ is halo.

In some embodiments, R¹ is fluoro.

In some embodiments, R¹ is chloro.

In some embodiments, R¹ is CN.

In some embodiments, R¹ is NO₂

In some embodiments, R¹ is COC₁-C₆ alkyl.

In some embodiments, R¹ is CO—C₆-C₁₀ aryl.

In some embodiments, R¹ is CO (5- to 10-membered heteroaryl).

In some embodiments, R¹ is CO₂C₁-C₆ alkyl.

In some embodiments, R¹ is CO₂C₃-C₈ cycloalkyl.

In some embodiments, R¹ is OCOC₁-C₆ alkyl.

In some embodiments, R¹ is OCOC₆-C₁₀ aryl.

In some embodiments, R¹ is OCO (5- to 10-membered heteroaryl).

In some embodiments, R¹ is OCO (3- to 7-membered heterocycloalkyl).

In some embodiments, R¹ is C₆-C₁₀ aryl.

In some embodiments, R¹ is phenyl.

In some embodiments, R¹ is 5- to 10-membered heteroaryl.

In some embodiments, R¹ is pyridyl (e.g., 4-pyridyl).

In some embodiments, R¹ is pyrazolyl (e.g., 1-pyrazolyl).

In some embodiments, R¹ is NH₂.

In some embodiments, R¹ is NHC₁-C₆ alkyl.

In some embodiments, R¹ is N(C₁-C₆ alkyl)₂.

In some embodiments, R¹ is CONR⁸R⁹.

In some embodiments, R¹ is SF₅.

In some embodiments, R¹ is SC₁-C₆ alkyl,

In some embodiments, R¹ is S(O₂)C₁-C₆ alkyl.

In some embodiments, R¹ is S(O₂)CH₃.

In some embodiments, R¹ is S(O₂)NR¹¹R¹².

In some embodiments, R¹ is S(O₂)N(CH₃)₂.

In some embodiments, R¹ is S(O)C₁-C₆ alkyl.

In some embodiments, R¹ is S(O)CH₃.

In some embodiments, R¹ is attached to a carbon of an aryl ring A.

In some embodiments, R¹ is attached to a carbon of a heteroaryl ring A.

In some embodiments, R¹ is attached to a nitrogen of a heteroaryl ringA.

Particular Embodiments Wherein m=1 and n=1:

In some embodiments, R¹ is C₁-C₆ alkyl optionally substituted with oneor more hydroxy, and R² is C₁-C₆ alkyl optionally substituted with oneor more hydroxy.

In some embodiments, R¹ is 1-hydroxy-2-methylpropan-2-yl, and R² ismethyl.

In some embodiments, R¹ is 2-hydroxy-2-propyl and R² is methyl.

In some embodiments, R¹ is 2-hydroxy-2-propyl and R² is isopropyl.

In some embodiments, R¹ is 2-hydroxy-2-propyl and R² is2-hydroxy-2-propyl.

In some embodiments, R¹ is 2-hydroxy-2-propyl and R² is 1-hydroxyethyl.

In some embodiments, R¹ is hydroxymethyl and R² is methyl.

In some embodiments, R¹ is 1-hydroxyethyl and R² is methyl.

In some embodiments, R¹ is 2-hydroxyethyl and R² is methyl.

In some embodiments, R¹ is 1-hydroxy-2-propyl and R² is methyl.

In some embodiments, R¹ is C₁-C₆ alkyl optionally substituted with oneor more hydroxy, and R² is C₆-C₁₀ aryl.

In some embodiments, R¹ is 2-hydroxy-2-propyl and R² is phenyl.

In some embodiments, R¹ is C₁-C₆ alkyl optionally substituted with oneor more hydroxy, and R² is 5- to 10-membered heteroaryl.

In some embodiments, R¹ is 2-hydroxy-2-propyl and R² is pyridyl.

In some embodiments, R¹ is 2-hydroxy-2-propyl and R² is pyrazolyl.

In some embodiments, R¹ is C₁-C₆ alkyl optionally substituted with oneor more hydroxy, and R² is SF₅.

In some embodiments, R¹ is C₁-C₆ alkyl optionally substituted with oneor more hydroxy, and R² is SC₁-C₆ alkyl,

In some embodiments, R¹ is C₁-C₆ alkyl optionally substituted with oneor more hydroxy, and R² is S(O₂)C₁-C₆ alkyl.

In some embodiments, R¹ is C₁-C₆ alkyl optionally substituted with oneor more hydroxy, and R² is S(O₂)CH₃.

In some embodiments, R¹ is C₁-C₆ alkyl optionally substituted with oneor more hydroxy, and R² is halo.

In some embodiments, R¹ is 2-hydroxy-2-propyl and R² is chloro.

In some embodiments, R¹ is 2-hydroxy-2-propyl and R² is fluoro.

In some embodiments, R¹ is C₃-C₇ cycloalkyl optionally substituted withone or more hydroxy, and R² is C₁-C₆ alkyl.

In some embodiments, R¹ is 1-hydroxy-1-cyclopropyl, and R² is methyl.

In some embodiments, R¹ is 1-hydroxy-1-cyclobutyl, and R² is methyl.

In some embodiments, R¹ is 1-hydroxy-1-cyclopentyl, and R² is methyl.

In some embodiments, R¹ is 1-hydroxy-1-cyclohexyl, and R² is methyl.

In some embodiments, R¹ is 3- to 7-membered heterocycloalkyl optionallysubstituted with one or more hydroxy, and R² is C₁-C₆ alkyl.

In some embodiments, R¹ is morpholinyl, and R² is methyl.

In some embodiments, R¹ is 1,3-dioxolan-2-yl, and R² is methyl.

In some embodiments, R¹ is 3- to 7-membered heterocycloalkyl optionallysubstituted with one or more hydroxy, and R² is halo.

In some embodiments, R¹ is 1,3-dioxolan-2-yl, and R² is fluoro.

In some embodiments, R¹ is 1,3-dioxolan-2-yl, and R² is chloro.

In some embodiments, R¹ is C₁-C₆ alkyl optionally substituted with oneor more oxo, and R² is methyl.

In some embodiments, R¹ is COCH₃, and R² is methyl.

In some embodiments, R¹ is C₁-C₆ alkyl optionally substituted with oneor more C₁-C₆ alkoxy, and R² is C₁-C₆ alkyl.

In some embodiments, R¹ is 2-methoxy-2-propyl, and R² is methyl.

In some embodiments, R¹ is C₁-C₆ alkyl optionally substituted with oneor more NR⁸R⁹, and R² is C₁-C₆ alkyl.

In some embodiments, R¹ is (dimethylamino)methyl, and R² is methyl.

In some embodiments, R¹ is C₁-C₆ alkyl optionally substituted with oneor more NR⁸R⁹, and R² is halo.

In some embodiments, R¹ is (dimethylamino)methyl, and R² is fluoro.

In some embodiments, R¹ is (dimethylamino)methyl, and R² is fluoro.

In some embodiments, R¹ is (methylamino)methyl, and R² is fluoro.

In some embodiments, R¹ is aminomethyl, and R² is fluoro.

In some embodiments, R¹ is C₁-C₆ alkyl, and R² is C₁-C₆ alkyl.

In some embodiments, R¹ is methyl, and R² is methyl.

In some embodiments, R² is 1-hydroxy-2-methylpropan-2-yl, and R¹ ismethyl.

In some embodiments, R² is 2-hydroxy-2-propyl and R¹ is methyl.

In some embodiments, R² is 2-hydroxy-2-propyl and R¹ is isopropyl.

In some embodiments, R² is 2-hydroxy-2-propyl and R¹ is 1-hydroxyethyl.

In some embodiments, R² is hydroxymethyl and R¹ is methyl.

In some embodiments, R² is 1-hydroxyethyl and R¹ is methyl.

In some embodiments, R² is 2-hydroxyethyl and R¹ is methyl.

In some embodiments, R² is 1-hydroxy-2-propyl and R¹ is methyl.

In some embodiments, R² is C₁-C₆ alkyl optionally substituted with oneor more hydroxy, and R¹ is C₆-C₁₀ aryl.

In some embodiments, R² is 2-hydroxy-2-propyl and R¹ is phenyl.

In some embodiments, R² is C₁-C₆ alkyl optionally substituted with oneor more hydroxy, and R¹ is 5- to 10-membered heteroaryl.

In some embodiments, R² is 2-hydroxy-2-propyl and R¹ is pyridyl.

In some embodiments, R² is 2-hydroxy-2-propyl and R¹ is pyrazolyl.

In some embodiments, R² is C₁-C₆ alkyl optionally substituted with oneor more hydroxy, and R¹ is SF₅.

In some embodiments, R² is C₁-C₆ alkyl optionally substituted with oneor more hydroxy, and R¹ is SC₁-C₆ alkyl.

In some embodiments, R² is C₁-C₆ alkyl optionally substituted with oneor more hydroxy, and R¹ is S(O₂)C₁-C₆ alkyl.

In some embodiments, R² is C₁-C₆ alkyl optionally substituted with oneor more hydroxy, and R¹ is S(O₂)CH₃.

In some embodiments, R² is C₁-C₆ alkyl optionally substituted with oneor more hydroxy, and R¹ is halo.

In some embodiments, R² is 2-hydroxy-2-propyl and R¹ is chloro.

In some embodiments, R² is 2-hydroxy-2-propyl and R¹ is fluoro.

In some embodiments, R² is C₃-C₇ cycloalkyl optionally substituted withone or more hydroxy, and R¹ is C₁-C₆ alkyl.

In some embodiments, R² is 1-hydroxy-1-cyclopropyl, and R¹ is methyl.

In some embodiments, R² is 1-hydroxy-1-cyclobutyl, and R¹ is methyl.

In some embodiments, R² is 1-hydroxy-1-cyclopentyl, and R¹ is methyl.

In some embodiments, R² is 1-hydroxy-1-cyclohexyl, and R¹ is methyl.

In some embodiments, R² is 3- to 7-membered heterocycloalkyl optionallysubstituted with one or more hydroxy, and R¹ is C₁-C₆ alkyl.

In some embodiments, R² is morpholinyl, and R¹ is methyl.

In some embodiments, R² is 1,3-dioxolan-2-yl, and R¹ is methyl.

In some embodiments, R² is 3- to 7-membered heterocycloalkyl optionallysubstituted with one or more hydroxy, and R¹ is halo.

In some embodiments, R² is 1,3-dioxolan-2-yl, and R¹ is fluoro.

In some embodiments, R² is 1,3-dioxolan-2-yl, and R¹ is chloro.

In some embodiments, R² is C₁-C₆ alkyl optionally substituted with oneor more oxo, and R¹ is methyl.

In some embodiments, R² is COCH₃, and R¹ is methyl.

In some embodiments, R² is C₁-C₆ alkyl optionally substituted with oneor more C₁-C₆ alkoxy, and R¹ is C₁-C₆ alkyl.

In some embodiments, R² is 2-methoxy-2-propyl, and R¹ is methyl.

In some embodiments, R² is C₁-C₆ alkyl optionally substituted with oneor more NR⁸R⁹, and R¹ is C₁-C₆ alkyl.

In some embodiments, R² is (dimethylamino)methyl, and R¹ is methyl.

In some embodiments, R² is C₁-C₆ alkyl optionally substituted with oneor more NR⁸R⁹, and R¹ is halo.

In some embodiments, R² is (dimethylamino)methyl, and R¹ is fluoro.

In some embodiments, R² is (methylamino)methyl, and R¹ is fluoro.

In some embodiments, R² is aminomethyl, and R¹ is fluoro.

In some embodiments, R² is C₁-C₆ alkoxy, and R¹ is C₁-C₆ alkyloptionally substituted with one or more NR⁸R⁹.

In some embodiments, R² is methoxy, and R¹ is (dimethylamino)methyl.

In some embodiments, R¹ and R² are each attached to a carbon of an arylring A.

In some embodiments, R¹ and R² are each attached to a carbon of aheteroaryl ring A.

In some embodiments, R¹ is attached to a carbon and R² is attached to anitrogen of a heteroaryl ring A.

In some embodiments, R² is attached to a carbon and R¹ is attached to anitrogen of a heteroaryl ring A.

In some embodiments, R¹ and R² are on adjacent atoms, and taken togetherwith the atoms connecting them, form a C₅ carbocyclic ring optionallysubstituted with one or more substituents independently selected fromhydroxy, halo, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹.

In some embodiments, R¹ and R² are on adjacent atoms, and taken togetherwith the atoms connecting them, form a C₅ aliphatic carbocyclic ring.

In some embodiments, R¹ and R² are on adjacent atoms, and taken togetherwith the atoms connecting them, form a C₆ carbocyclic ring optionallysubstituted with one or more substituents independently selected fromhydroxy, halo, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹.

In some embodiments, R¹ and R² are on adjacent atoms, and taken togetherwith the atoms connecting them, form a C₆ aliphatic carbocyclic ring.

In some embodiments, R¹ and R² are on adjacent atoms, and taken togetherwith the atoms connecting them, form a C₆ aromatic carbocyclic ring.

In some embodiments, R¹ and R² are on adjacent atoms, and taken togetherwith the atoms connecting them, form a 5-membered heterocyclic ringcontaining 1 or 2 heteroatoms independently selected from O, N, and S,optionally substituted with one or more substituents independentlyselected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹,═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹.

In some embodiments, R¹ and R² are on adjacent atoms, and taken togetherwith the atoms connecting them, form a 5-membered aliphatic heterocyclicring containing 1 or 2 heteroatoms independently selected from O, N, andS.

In some embodiments, R¹ and R² are on adjacent atoms, and taken togetherwith the atoms connecting them, form a 5-membered heteroaromatic ringcontaining 1 or 2 heteroatoms independently selected from O, N, and S.

In some embodiments, R¹ and R² are on adjacent atoms, and taken togetherwith the atoms connecting them, form a 6-membered heterocyclic ringcontaining 1 or 2 heteroatoms independently selected from O, N, and S,optionally substituted with one or more substituents independentlyselected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹,═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹.

In some embodiments, R¹ and R² are on adjacent atoms, and taken togetherwith the atoms connecting them, form a 6-membered aliphatic heterocyclicring containing 1 or 2 heteroatoms independently selected from O, N, andS.

In some embodiments, R¹ and R² are on adjacent atoms, and taken togetherwith the atoms connecting them, form a 6-membered heteroaromatic ringcontaining 1 or 2 heteroatoms independently selected from O, N, and S.

In some embodiments, R¹ and R² are different.

In some embodiments, R¹ and R² are different, and R² comprises acarbonyl group.

In some embodiments, R¹ and R² are different, and R² comprises 1 or 2(e.g., 1) nitrogen atoms.

In some embodiments, R¹ and R² are different, and R² comprises 1 or 2(e.g., 1) oxygen atoms.

In some embodiments, R¹ and R² are different, and R² comprises a sulfuratom.

In some embodiments, R² and R¹ are different, and R² comprises acarbonyl group.

In some embodiments, R² and R¹ are different, and R² comprises 1 or 2(e.g., 1) nitrogen atoms.

In some embodiments, R² and R¹ are different, and R² comprises 1 or 2(e.g., 1) oxygen atoms.

In some embodiments, R² and R¹ are different, and R² comprises a sulfuratom.

In some embodiments, R¹ and R² are the same.

In some embodiments, R¹ is para or meta to R².

In some embodiments, R¹ is para or ortho to R².

In some embodiments, R¹ is ortho or meta to R². In some embodiments, R¹is para to R².

In some embodiments, R¹ is meta to R².

In some embodiments, R¹ is ortho to R².

The Variables o and p

In some embodiments, o=1 or 2.

In some embodiments, o=1.

In some embodiments, o=2.

In some embodiments, p=0, 1, 2, or 3.

In some embodiments, p=0.

In some embodiments, p=1.

In some embodiments, p=2.

In some embodiments, o=1 and p=0.

In some embodiments, o=2 and p=0.

In some embodiments, o=1 and p=1.

In some embodiments, o=1 and p=2.

In some embodiments, o=2 and p=1.

In some embodiments, o=2 and p=2.

In some embodiments, o=2 and p=3.

The Ring B and Substitutions on the Ring B

In some embodiments, B is a 5- to 10-membered monocyclic or bicyclicheteroaryl or a C₆-C₁₀ monocyclic or bicyclic aryl, such as phenyl.

In some embodiments, B is a 5- to 6-membered monocyclic heteroaryl or aC₆ monocyclic aryl.

In some embodiments, B is a 5- to 10-membered monocyclic or bicyclicheteroaryl.

In some embodiments, B is a C₆-C₁₀ monocyclic or bicyclic aryl.

In some embodiments, B is a 5-membered heteroaryl.

In some embodiments, B is a 7-10 membered monocyclic or bicyclicheteroaryl.

In some embodiments, B is phenyl substituted with 1 or 2 R⁶ andoptionally substituted with 1, 2, or 3 R⁷.

In some embodiments, B is pyridyl substituted with 1 or 2 R⁶ andoptionally substituted with 1, 2, or 3 R⁷.

In some embodiments, B is indazolyl substituted with 1 or 2 R⁶ andoptionally substituted with 1, 2, or 3 R⁷.

In some embodiments, B is pyrazolyl substituted with 1 or 2 R⁶ andoptionally substituted with 1 or 2 R⁷.

In some embodiments, B is phenyl, o is 1 or 2, and p is 0, 1, 2, or 3.

In some embodiments, B is phenyl, o is 1, and p is 0, 1, 2, or 3.

In some embodiments, B is phenyl, o is 2, and p is 0, 1, 2, or 3.

In some embodiments, B is one of the rings disclosed hereinbelow,substituted as disclosed hereinbelow, wherein in each case the bond thatis shown as being broken by the wavy line

connects B to the NH(CO) group of Formula AA.

In some embodiments, the substituted ring B

is

In some embodiments, the substituted ring B

is

In some embodiments, the substituted ring B is

In some embodiments, the substituted ring B is

In some embodiments, the substituted ring B is

In some embodiments, the substituted ring B is

In some embodiments, the substituted ring B is

In some embodiments, the substituted ring B is

In some embodiments, the substituted ring B is

In some embodiments, the substituted ring B is

In some embodiments, the substituted ring B is

In some embodiments, the substituted ring B is

In some embodiments, the substituted ring B is

In some embodiments, the substituted ring B is

In some embodiments, the substituted ring B is

In some embodiments, the substituted ring B is

In some embodiments, the substituted ring B is

In some embodiments, the substituted ring B is

In some embodiments, the substituted ring B is

In some embodiments, the substituted ring B is

In some embodiments, the substituted ring B is

In some embodiments, the substituted ring B is

In some embodiments, the substituted ring B is

In some embodiments, the substituted ring B is

In some embodiments, the substituted ring B is

In some embodiments, the substituted ring B is

In some embodiments, the substituted ring B is

In some embodiments, the substituted ring B is

In some embodiments, the substituted ring B is

In some embodiments, the substituted ring B is

In some embodiments, the substituted ring B is

In some embodiments, the substituted ring B is

In some embodiments, the substituted ring B is

In some embodiments, the substituted ring B is

In some embodiments, the substituted ring B is

In some embodiments, the substituted ring B is

In some embodiments, the substituted ring B is

In some embodiments, the substituted ring B is

In some embodiments, the substituted ring B is

In some embodiments, the substituted ring B is

In some embodiments, the substituted ring B is

In some embodiments, the substituted ring B is

In some embodiments, the substituted ring B is

In some embodiments, the substituted ring B is

In some embodiments, the substituted ring B is

In some embodiments, the substituted ring B is

In some embodiments, the substituted ring B is

In some embodiments, the substituted ring B is

In some embodiments, the substituted ring B is

In some embodiments, the substituted ring B is

The Groups R⁶ and R⁷

In some embodiments,

R⁶ and R⁷ are each independently selected from C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halo, CN, NO₂, COC₁-C₆ alkyl,CO₂C₁-C₆ alkyl, CO₂C₃-C₈ cycloalkyl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO (3- to 7-membered heterocycloalkyl),C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, NH₂, NHC₁-C₆ alkyl, N(C₁-C₆alkyl)₂, CONR⁸R⁹, SF₅, S(O₂)C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl and 3- to10-membered heterocycloalkyl, and a C₂-C₆ alkenyl,wherein R⁶ and R⁷ are each optionally substituted with one or moresubstituents independently selected fromhydroxy, halo, CN, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, NR¹⁰ COOC₁-C₆alkyl, CONR⁸R⁹, 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to10-membered heteroaryl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO (5- to10-membered heteroaryl), OCO (3- to 7-membered heterocycloalkyl),NHCOC₁-C₆ alkyl, NHCOC₆-C₁₀ aryl, NHCO (5- to 10-membered heteroaryl),NHCO (3- to 7-membered heterocycloalkyl), NHCOC₂-C₆ alkynyl,C₆-C₁₀ aryloxy, and S(O₂)C₁-C₆ alkyl; and wherein the C₁-C₆ alkyl orC₁-C₆ alkoxy that R⁶ or R⁷ is substituted with is optionally substitutedwith one or more hydroxyl, C₆-C₁₀ aryl or NR⁸R⁹, or wherein R⁶ or R⁷ isoptionally fused to a five- to -seven-membered carbocyclic ring orheterocyclic ring containing one or two heteroatoms independentlyselected from oxygen, sulfur and nitrogen;

-   -   wherein the 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5-        to 10-membered heteroaryl, NHCOC₆-C₁₀ aryl, NHCO (5- to        10-membered heteroaryl) and NHCO (3- to 7-membered        heterocycloalkyl) are optionally substituted with one or more        substituents independently selected from halo, C₁-C₆ alkyl, and        OC₁-C₆ alkyl;        or at least one pair of R⁶ and R⁷ on adjacent atoms, taken        together with the atoms connecting them, independently form at        least one C₄-C₈ carbocyclic ring or at least one 5- to        8-membered heterocyclic ring containing 1 or 2 heteroatoms        independently selected from O, N, and S, wherein the carbocyclic        ring or heterocyclic ring is optionally independently        substituted with one or more substituents independently selected        from hydroxy, hydroxymethyl, halo, oxo, C₁-C₆ alkyl, C₁-C₆        alkoxy, NR⁸R⁹, CH₂NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and        CONR⁸R⁹.

In some embodiments,

R⁶ and R⁷ are each independently selected from C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halo, CN, NO₂, COC₁-C₆ alkyl,CO₂C₁-C₆ alkyl, CO₂C₃-C₈ cycloalkyl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO (3- to 7-membered heterocycloalkyl),C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, NH₂, NHC₁-C₆ alkyl, N(C₁-C₆alkyl)₂, CONR⁸R⁹, SF₅, S(O₂)C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl and 3- to10-membered heterocycloalkyl, and a C₂-C₆ alkenyl,wherein R⁶ and R⁷ are each optionally substituted with one or moresubstituents independently selected fromhydroxy, halo, CN, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, NR¹⁰ COOC₁-C₆alkyl, CONR⁸R⁹, 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to10-membered heteroaryl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO (5- to10-membered heteroaryl), OCO (3- to 7-membered heterocycloalkyl),NHCOC₁-C₆ alkyl, NHCOC₆-C₁₀ aryl, NHCO (5- to 10-membered heteroaryl),NHCO (3- to 7-membered heterocycloalkyl), NHCOC₂-C₆ alkynyl,C₆-C₁₀ aryloxy, and S(O₂)C₁-C₆ alkyl; and wherein the C₁-C₆ alkyl orC₁-C₆ alkoxy that R⁶ or R⁷ is substituted with is optionally substitutedwith one or more hydroxyl, C₆-C₁₀ aryl or NR⁸R⁹, or wherein R⁶ or R⁷ isoptionally fused to a five- to -seven-membered carbocyclic ring orheterocyclic ring containing one or two heteroatoms independentlyselected from oxygen, sulfur and nitrogen;

-   -   wherein the 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5-        to 10-membered heteroaryl, NHCOC₆-C₁₀ aryl, NHCO (5- to        10-membered heteroaryl) and NHCO (3- to 7-membered        heterocycloalkyl) are optionally substituted with one or more        substituents independently selected from halo, C₁-C₆ alkyl, and        OC₁-C₆ alkyl;        or at least one pair of R⁶ and R⁷ on adjacent atoms, taken        together with the atoms connecting them, independently form at        least one C₄-C₆ aliphatic carbocyclic ring or at least one 5- to        6-membered heterocyclic ring containing 1 or 2 heteroatoms        independently selected from O, N, and S, wherein the carbocyclic        ring or heterocyclic ring is optionally independently        substituted with one or more substituents independently selected        from hydroxy, hydroxymethyl, halo, oxo, C₁-C₆ alkyl, C₁-C₆        alkoxy, NR⁸R⁹, CH₂NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and        CONR⁸R⁹.

In some embodiments,

R⁶ and R⁷ are each independently selected from C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halo, CN, NO₂, COC₁-C₆ alkyl,CO₂C₁-C₆ alkyl, CO₂C₃-C₈ cycloalkyl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO (3- to 7-membered heterocycloalkyl),C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, NH₂, NHC₁-C₆ alkyl, N(C₁-C₆alkyl)₂, CONR⁸R⁹, SF₅, SC₁-C₆ alkyl, S(O₂)C₁-C₆ alkyl, C₃-C₇ cycloalkyland 3- to 7-membered heterocycloalkyl,wherein the C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₇ cycloalkyl and 3- to7-membered heterocycloalkyl is optionally substituted with one or moresubstituents each independently selected from hydroxy, halo, CN, oxo,C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, CONR⁸R⁹, 3- to7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl,OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO (5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC₁-C₆ alkyl, NHCOC₆-C₁₀ aryl,NHCO (5- to 10-membered heteroaryl), NHCO (3- to 7-memberedheterocycloalkyl), and NHCOC₂-C₆ alkynyl;

-   -   wherein the 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5-        to 10-membered heteroaryl, NHCOC₆-C₁₀ aryl, NHCO (5- to        10-membered heteroaryl) and NHCO (3- to 7-membered        heterocycloalkyl) are optionally substituted with one or more        substituents independently selected from halo, C₁-C₆ alkyl, and        OC₁-C₆ alkyl;        or at least one pair of R⁶ and R⁷ on adjacent atoms, taken        together with the atoms connecting them, independently form at        least one C₄-C₈ carbocyclic ring or at least one 5- to        8-membered heterocyclic ring containing 1 or 2 heteroatoms        independently selected from O, N, and S, wherein the carbocyclic        ring or heterocyclic ring is optionally independently        substituted with one or more substituents independently selected        from hydroxy, hydroxymethyl, halo, oxo, C₁-C₆ alkyl, C₁-C₆        alkoxy, NR⁸R⁹, CH₂NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and        CONR⁸R⁹.

In some embodiments,

R⁶ and R⁷ are each independently selected from C₁-C₆ haloalkyl, C₁-C₆alkoxy, C₁-C₆ haloalkoxy, halo, CN, NO₂, COC₁-C₆ alkyl, CO₂C₁-C₆ alkyl,CO₂C₃-C₈ cycloalkyl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO (5- to10-membered heteroaryl), OCO (3- to 7-membered heterocycloalkyl), C₆-C₁₀aryl, 5- to 10-membered heteroaryl, NH₂, NHC₁-C₆ alkyl, N(C₁-C₆ alkyl)₂,CONR⁸R⁹, SF₅, SC₁-C₆ alkyl, S(O₂)C₁-C₆ alkyl, C₃-C₇ cycloalkyl and 3- to7-membered heterocycloalkyl,wherein the C₃-C₇ cycloalkyl, C₁-C₆ haloalkyl, and 3- to 7-memberedheterocycloalkyl is optionally substituted with one or more substituentseach independently selected from hydroxy, halo, CN, oxo, C₁-C₆ alkyl,C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, CONR⁸R⁹, 3- to 7-memberedheterocycloalkyl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆alkyl, OCOC₆-C₁₀ aryl, OCO (5- to 10-membered heteroaryl), OCO (3- to7-membered heterocycloalkyl), NHCOC₁-C₆ alkyl, NHCOC₆-C₁₀ aryl, NHCO (5-to 10-membered heteroaryl), NHCO (3- to 7-membered heterocycloalkyl),and NHCOC₂-C₆ alkynyl;

-   -   wherein the 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5-        to 10-membered heteroaryl, NHCOC₆-C₁₀ aryl, NHCO (5- to        10-membered heteroaryl) and NHCO (3- to 7-membered        heterocycloalkyl) are optionally substituted with one or more        substituents independently selected from halo, C₁-C₆ alkyl, and        OC₁-C₆ alkyl;        or at least one pair of R⁶ and R⁷ on adjacent atoms, taken        together with the atoms connecting them, independently form at        least one C₄-C₈ carbocyclic ring or at least one 5- to        8-membered heterocyclic ring containing 1 or 2 heteroatoms        independently selected from O, N, and S, wherein the carbocyclic        ring or heterocyclic ring is optionally independently        substituted with one or more substituents independently selected        from hydroxy, hydroxymethyl, halo, oxo, C₁-C₆ alkyl, C₁-C₆        alkoxy, NR⁸R⁹, CH₂NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and        CONR⁸R⁹.

In some embodiments,

R⁶ and R⁷ are each independently selected from C₁-C₆ alkyl, halo, CN,NO₂, COC₁-C₆ alkyl, CO₂C₁-C₆ alkyl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO (3- to 7-membered heterocycloalkyl),C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, NH₂, NHC₁-C₆ alkyl, N(C₁-C₆alkyl)₂, CONR⁸R⁹, SF₅, SC₁-C₆ alkyl, S(O₂)C₁-C₆ alkyl, C₃-C₇ cycloalkyland 3- to 7-membered heterocycloalkyl,wherein the C₁-C₆ alkyl, C₃-C₇ cycloalkyl and 3- to 7-memberedheterocycloalkyl is optionally substituted with one or more substituentseach independently selected from hydroxy, halo, CN, oxo, C₁-C₆ alkyl,C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰ COOC₁-C₆ alkyl, CONR⁸R⁹, 3- to 7-memberedheterocycloalkyl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆alkyl, OCOC₆-C₁₀ aryl, OCO (5- to 10-membered heteroaryl), OCO (3- to7-membered heterocycloalkyl), NHCOC₁-C₆ alkyl, NHCOC₆-C₁₀ aryl, NHCO (5-to 10-membered heteroaryl), NHCO (3- to 7-membered heterocycloalkyl),and NHCOC₂-C₆ alkynyl;

-   -   wherein the 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5-        to 10-membered heteroaryl, NHCOC₆-C₁₀ aryl, NHCO (5- to        10-membered heteroaryl) and NHCO (3- to 7-membered        heterocycloalkyl) are optionally substituted with one or more        substituents independently selected from halo, C₁-C₆ alkyl, and        OC₁-C₆ alkyl;        or at least one pair of R⁶ and R⁷ on adjacent atoms, taken        together with the atoms connecting them, independently form at        least one C₄-C₈ carbocyclic ring or at least one 5- to        8-membered heterocyclic ring containing 1 or 2 heteroatoms        independently selected from O, N, and S, wherein the carbocyclic        ring or heterocyclic ring is optionally independently        substituted with one or more substituents independently selected        from hydroxy, hydroxymethyl, halo, oxo, C₁-C₆ alkyl, C₁-C₆        alkoxy, NR⁸R⁹, CH₂NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and        CONR⁸R⁹.

In some embodiments,

R⁶ and R⁷ are each independently selected from C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halo, CN, NO₂, COC₁-C₆ alkyl,CO₂C₁-C₆ alkyl, CO₂C₃-C₈ cycloalkyl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO (3- to 7-membered heterocycloalkyl),C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, NH₂, NHC₁-C₆ alkyl, N(C₁-C₆alkyl)₂, CONR⁸R⁹, SF₅, SC₁-C₆ alkyl, S(O₂)C₁-C₆ alkyl, C₃-C₇ cycloalkyland 3- to 7-membered heterocycloalkyl,wherein the C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₇ cycloalkyl, and 3- to7-membered heterocycloalkyl is optionally substituted with one or moresubstituents each independently selected from hydroxy, halo, CN, oxo,C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, CONR⁸R⁹, 3- to7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl,OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO (5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC₁-C₆ alkyl, NHCOC₆-C₁₀ aryl,NHCO (5- to 10-membered heteroaryl), NHCO (3- to 7-memberedheterocycloalkyl), and NHCOC₂-C₆ alkynyl;

-   -   wherein the 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5-        to 10-membered heteroaryl, NHCOC₆-C₁₀ aryl, NHCO (5- to        10-membered heteroaryl) and NHCO (3- to 7-membered        heterocycloalkyl) are unsubstituted;        or at least one pair of R⁶ and R⁷ on adjacent atoms, taken        together with the atoms connecting them, independently form at        least one C₄-C₈ carbocyclic ring or at least one 5- to        8-membered heterocyclic ring containing 1 or 2 heteroatoms        independently selected from O, N, and S, wherein the carbocyclic        ring or heterocyclic ring is optionally independently        substituted with one or more substituents independently selected        from hydroxy, hydroxymethyl, halo, oxo, C₁-C₆ alkyl, C₁-C₆        alkoxy, NR⁸R⁹, CH₂NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and        CONR⁸R⁹.

In some embodiments,

R⁶ and R⁷ are each independently selected from C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halo, CN, NO₂, COC₁-C₆ alkyl,CO₂C₁-C₆ alkyl, CO₂C₃-C₈ cycloalkyl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO (3- to 7-membered heterocycloalkyl),C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, NH₂, NHC₁-C₆ alkyl, N(C₁-C₆alkyl)₂, CONR⁸R⁹, SF₅, SC₁-C₆ alkyl, S(O₂)C₁-C₆ alkyl, C₃-C₇ cycloalkyland 3- to 7-membered heterocycloalkyl,wherein the C₁-C₆ alkyl, C₃-C₇ cycloalkyl and 3- to 7-memberedheterocycloalkyl are each unsubstituted;or at least one pair of R⁶ and R⁷ on adjacent atoms, taken together withthe atoms connecting them, independently form at least one C₄-C₈carbocyclic ring or at least one 5- to 8-membered heterocyclic ringcontaining 1 or 2 heteroatoms independently selected from O, N, and S,wherein the carbocyclic ring or heterocyclic ring is optionallyindependently substituted with one or more substituents independentlyselected from hydroxy, hydroxymethyl, halo, oxo, C₁-C₆ alkyl, C₁-C₆alkoxy, NR⁸R⁹, CH₂NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, andCONR⁸R⁹.

In some embodiments,

R⁶ is independently selected from C₁-C₆ alkyl, C₃-C₇ cycloalkyl, C₁-C₆haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halo, CN, C₆-C₁₀ aryl, 5- to10-membered heteroaryl, CO—C₁-C₆ alkyl; CONR⁸R⁹, and 4- to 6-memberedheterocycloalkyl,wherein the C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₇ cycloalkyl and 4- to6-membered heterocycloalkyl is optionally substituted with one or moresubstituents each independently selected from hydroxy, halo, CN, oxo,C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, CONR⁸R⁹, 4- to6-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl,OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO (5- to 10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl), NHCOC₁-C₆ alkyl, NHCOC₆-C₁₀ aryl,NHCO (5- to 10-membered heteroaryl), NHCO (4- to 6-memberedheterocycloalkyl), and NHCOC₂-C₆ alkynyl;

-   -   and R⁷ is independently selected from C₁-C₆ alkyl, C₁-C₆        haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halo, CN, COC₁-C₆        alkyl, CO₂C₁-C₆ alkyl, CO₂C₃-C₆ cycloalkyl, OCOC₁-C₆ alkyl,        OCOC₆-C₁₀ aryl, OCO (5- to 10-membered heteroaryl), OCO (3- to        7-membered heterocycloalkyl), C₆-C₁₀ aryl, 5- to 10-membered        heteroaryl, CONR⁸R⁹, SF₅, S(O₂)C₁-C₆ alkyl, C₃-C₇ cycloalkyl and        4- to 6-membered heterocycloalkyl, wherein the C₁-C₆ alkyl is        optionally substituted with one to two C₁-C₆ alkoxy;        or R⁶ and R⁷, taken together with the atoms connecting them,        independently form C₄-C₇ carbocyclic ring or at least one        5-to-7-membered heterocyclic ring containing 1 or 2 heteroatoms        independently selected from O, N, and S, wherein the carbocyclic        ring or heterocyclic ring is optionally independently        substituted with one or more substituents independently selected        from hydroxy, halo, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹,        ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹.

In some embodiments,

R⁶ and R⁷ are each independently selected from C₁-C₆ alkyl, C₁-C₆alkoxy, halo, CN, NO₂, COC₁-C₆ alkyl, CO₂C₁-C₆ alkyl, C₆-C₁₀ aryl, 5- to10-membered heteroaryl, CONR⁸R⁹, and 3- to 7-membered heterocycloalkyl,wherein the C₁-C₆ alkyl and 3- to 7-membered heterocycloalkyl isoptionally substituted with one or more substituents each independentlyselected from hydroxy or oxo,or at least one pair of R⁶ and R⁷ on adjacent atoms, taken together withthe atoms connecting them, independently form at least one C₄-C₈carbocyclic ring, wherein the carbocyclic ring is optionallyindependently substituted with one or more hydroxy or oxo.

In some embodiments,

R⁶ and R⁷ are each independently selected from C₁-C₆ alkyl, C₁-C₆alkoxy, halo, CN, NO₂, COC₁-C₆ alkyl, CO₂C₁-C₆ alkyl, C₆-C₁₀ aryl, 5- to10-membered heteroaryl, CONR⁸R⁹, and 3- to 7-membered heterocycloalkyl,wherein the C₁-C₆ alkyl and 3- to 7-membered heterocycloalkyl isoptionally substituted with one or more substituents each independentlyselected from hydroxy or oxo,or at least one pair of R⁶ and R⁷ on adjacent atoms, taken together withthe atoms connecting them, independently form at least one C₄-C₆aliphatic carbocyclic ring, wherein the carbocyclic ring is optionallyindependently substituted with one or more hydroxy or oxo.

In some embodiments,

R⁶ and R⁷ are each independently selected from C₁-C₆ alkyl, C₁-C₆alkoxy, halo, CN, NO₂, COC₁-C₆ alkyl, CO₂C₁-C₆ alkyl, C₆-C₁₀ aryl, 5- to10-membered heteroaryl, CONR⁸R⁹, and 3- to 7-membered heterocycloalkyl,wherein the C₁-C₆ alkyl and 3- to 7-membered heterocycloalkyl isoptionally substituted with one or more substituents each independentlyselected from hydroxy or oxo,or at least one pair of R⁶ and R⁷ on adjacent atoms, taken together withthe atoms connecting them, independently form at least one 5- to8-membered heterocyclic ring containing 1 or 2 heteroatoms independentlyselected from O, N, and S, wherein the heterocyclic ring is optionallyindependently substituted with one or more hydroxy or oxo.

In some embodiments,

R⁶ and R⁷ are each independently selected from C₁-C₆ alkyl, C₁-C₆alkoxy, halo, CN, NO₂, COC₁-C₆ alkyl, CO₂C₁-C₆ alkyl, C₆-C₁₀ aryl, 5- to10-membered heteroaryl, CONR⁸R⁹, and 3- to 7-membered heterocycloalkyl,wherein the C₁-C₆ alkyl and 3- to 7-membered heterocycloalkyl isoptionally substituted with one or more substituents each independentlyselected from hydroxy or oxo,or at least one pair of R⁶ and R⁷ on adjacent atoms, taken together withthe atoms connecting them, independently form at least one C₄-C₈carbocyclic ring, wherein the carbocyclic ring is optionallyindependently substituted with one or more hydroxy or oxo.

In some embodiments,

at least one pair of R⁶ and R⁷ on adjacent atoms, taken together withthe atoms connecting them, independently form at least one C₄-C₆aliphatic carbocyclic ring, wherein the carbocyclic ring is optionallyindependently substituted with one or more hydroxy or oxo.

In some embodiments,

at least one pair of R⁶ and R⁷ on adjacent atoms, taken together withthe atoms connecting them, independently form at least one C₄ aliphaticcarbocyclic ring, wherein the carbocyclic ring is optionallyindependently substituted with one or more hydroxy or oxo.

In some embodiments,

at least one pair of R⁶ and R⁷ on adjacent atoms, taken together withthe atoms connecting them, independently form at least one C₅ aliphaticcarbocyclic ring, wherein the carbocyclic ring is optionallyindependently substituted with one or more hydroxy or oxo.

In some embodiments,

at least one pair of R⁶ and R⁷ on adjacent atoms, taken together withthe atoms connecting them, independently form at least one C₆ aliphaticcarbocyclic ring, wherein the carbocyclic ring is optionallyindependently substituted with one or more hydroxy or oxo.

In some embodiments,

at least one pair of R⁶ and R⁷ on adjacent atoms, taken together withthe atoms connecting them, independently form at least one 5- to6-membered heterocyclic ring containing 1 heteroatom independentlyselected from O, N, and S, wherein the heterocyclic ring is optionallyindependently substituted with one or more hydroxy or oxo.

In some embodiments,

at least one pair of R⁶ and R⁷ on adjacent atoms, taken together withthe atoms connecting them, independently form at least one 5-memberedheterocyclic ring containing 1 heteroatom independently selected from O,N, and S, wherein the heterocyclic ring is optionally independentlysubstituted with one or more hydroxy or oxo.

In some embodiments,

at least one pair of R⁶ and R⁷ on adjacent atoms, taken together withthe atoms connecting them, independently form at least one 6-memberedheterocyclic ring containing 1 heteroatom independently selected from O,N, and S, wherein the heterocyclic ring is optionally independentlysubstituted with one or more hydroxy or oxo.

In some embodiments,

at least one pair of R⁶ and R⁷ on adjacent atoms, taken together withthe atoms connecting them, independently form at least one C₄ aliphaticcarbocyclic ring, wherein the carbocyclic ring is optionallyindependently substituted with one or more C₁-C₆ alkyl.

In some embodiments,

at least one pair of R⁶ and R⁷ on adjacent atoms, taken together withthe atoms connecting them, independently form at least one C₅ aliphaticcarbocyclic ring, wherein the carbocyclic ring is optionallyindependently substituted with one or more C₁-C₆ alkyl.

In some embodiments,

at least one pair of R⁶ and R⁷ on adjacent atoms, taken together withthe atoms connecting them, independently form at least one C₆ aliphaticcarbocyclic ring, wherein the carbocyclic ring is optionallyindependently substituted with one or more C₁-C₆ alkyl.

In some embodiments,

at least one pair of R⁶ and R⁷ on adjacent atoms, taken together withthe atoms connecting them, independently form at least one 5- to6-membered heterocyclic ring containing 1 heteroatom independentlyselected from O, N, and S, wherein the heterocyclic ring is optionallyindependently substituted with one or more C₁-C₆ alkyl.

In some embodiments,

at least one pair of R⁶ and R⁷ on adjacent atoms, taken together withthe atoms connecting them, independently form at least one 5-memberedheterocyclic ring containing 1 heteroatom independently selected from O,N, and S, wherein the heterocyclic ring is optionally independentlysubstituted with one or more C₁-C₆ alkyl.

In some embodiments,

at least one pair of R⁶ and R⁷ on adjacent atoms, taken together withthe atoms connecting them, independently form at least one 6-memberedheterocyclic ring containing 1 heteroatom independently selected from O,N, and S, wherein the heterocyclic ring is optionally independentlysubstituted with one or more C₁-C₆ alkyl.

In some embodiments, o=1; p=0; and

R⁶ is selected from C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆haloalkoxy, halo, CN, NO₂, COC₁-C₆ alkyl, CO₂C₁-C₆ alkyl, CO₂C₃-C₈cycloalkyl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO (5- to 10-memberedheteroaryl), OCO (3- to 7-membered heterocycloalkyl), C₆-C₁₀ aryl, 5- to10-membered heteroaryl, NH₂, NHC₁-C₆ alkyl, N(C₁-C₆ alkyl)₂, CONR⁸R⁹,SF₅, SC₁-C₆ alkyl, S(O₂)C₁-C₆ alkyl, C₃-C₇ cycloalkyl and 3- to7-membered heterocycloalkyl,wherein the C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₇ cycloalkyl and 3- to7-membered heterocycloalkyl is optionally substituted with one or moresubstituents each independently selected from hydroxy, halo, CN, oxo,C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, CONR⁸R⁹, 3- to7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl,OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO (5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC₁-C₆ alkyl, NHCOC₆-C₁₀ aryl,NHCO (5- to 10-membered heteroaryl), NHCO (3- to 7-memberedheterocycloalkyl), and NHCOC₂-C₆ alkynyl;

-   -   wherein the 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5-        to 10-membered heteroaryl, NHCOC₆-C₁₀ aryl, NHCO (5- to        10-membered heteroaryl) and NHCO (3- to 7-membered        heterocycloalkyl) are optionally substituted with one or more        substituents independently selected from halo, C₁-C₆ alkyl, and        OC₁-C₆ alkyl.

In some embodiments, o=1; p=1; and

R⁶ and R⁷ are each independently selected from C₁-C₆ alkyl, C₁-C₆alkoxy, halo, CN, NO₂, COC₁-C₆ alkyl, CO₂C₁-C₆ alkyl, C₆-C₁₀ aryl, 5- to10-membered heteroaryl, CONR⁸R⁹, and 3- to 7-membered heterocycloalkyl,wherein the C₁-C₆ alkyl and 3- to 7-membered heterocycloalkyl isoptionally substituted with one or more substituents each independentlyselected from hydroxy or oxo,or at least one pair of R⁶ and R⁷ on adjacent atoms, taken together withthe atoms connecting them, independently form at least one C₄-C₈carbocyclic ring, wherein the carbocyclic ring is optionallyindependently substituted with one or more hydroxy or oxo.

In some embodiments, o=1 or 2; p=1, 2, or 3; and

R⁶ and R⁷ are each independently selected from C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halo, CN, NO₂, COC₁-C₆ alkyl,CO₂C₁-C₆ alkyl, CO₂C₃-C₈ cycloalkyl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO (3- to 7-membered heterocycloalkyl),C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, NH₂, NHC₁-C₆ alkyl, N(C₁-C₆alkyl)₂, CONR⁸R⁹, SF₅, SC₁-C₆ alkyl, S(O₂)C₁-C₆ alkyl, C₃-C₇ cycloalkyland 3- to 7-membered heterocycloalkyl,wherein the C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₇ cycloalkyl, and 3- to7-membered heterocycloalkyl is optionally substituted with one or moresubstituents each independently selected from hydroxy, halo, CN, oxo,C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, CONR⁸R⁹, 3- to7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl,OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO (5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC₁-C₆ alkyl, NHCOC₆-C₁₀ aryl,NHCO (5- to 10-membered heteroaryl), NHCO (3- to 7-memberedheterocycloalkyl), and NHCOC₂-C₆ alkynyl;

-   -   wherein the 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5-        to 10-membered heteroaryl, NHCOC₆-C₁₀ aryl, NHCO (5- to        10-membered heteroaryl) and NHCO (3- to 7-membered        heterocycloalkyl) are optionally substituted with one or more        substituents independently selected from halo, C₁-C₆ alkyl, and        OC₁-C₆ alkyl.

In some embodiments, o=2; p=1; and

each R⁶ is independently selected from C₁-C₆ alkyl, C₃-C₇ cycloalkyl,C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halo, CN, C₆-C₁₀ aryl,5- to 10-membered heteroaryl, CO—C₁-C₆ alkyl; CONR⁸R⁹, and 4- to6-membered heterocycloalkyl,wherein the C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₇ cycloalkyl and 4- to6-membered heterocycloalkyl is optionally substituted with one or moresubstituents each independently selected from hydroxy, halo, CN, oxo,C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, CONR⁸R⁹, 4- to6-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl,OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO (5- to 10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl), NHCOC₁-C₆ alkyl, NHCOC₆-C₁₀ aryl,NHCO (5- to 10-membered heteroaryl), NHCO (4- to 6-memberedheterocycloalkyl), and NHCOC₂-C₆ alkynyl;

-   -   and R⁷ is independently selected from C₁-C₆ alkyl, C₁-C₆        haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halo, CN, COC₁-C₆        alkyl, CO₂C₁-C₆ alkyl, CO₂C₃-C₆ cycloalkyl, OCOC₁-C₆ alkyl,        OCOC₆-C₁₀ aryl, OCO (5- to 10-membered heteroaryl), OCO (3- to        7-membered heterocycloalkyl), C₆-C₁₀ aryl, 5- to 10-membered        heteroaryl, CONR⁸R⁹, SF₅, S(O₂)C₁-C₆ alkyl, C₃-C₇ cycloalkyl and        4- to 6-membered heterocycloalkyl, wherein the C₁-C₆ alkyl is        optionally substituted with one to two C₁-C₆ alkoxy;        or R⁶ and R⁷, taken together with the atoms connecting them,        independently form C₄-C₇ carbocyclic ring or at least one        5-to-7-membered heterocyclic ring containing 1 or 2 heteroatoms        independently selected from O, N, and S, wherein the carbocyclic        ring or heterocyclic ring is optionally independently        substituted with one or more substituents independently selected        from hydroxy, halo, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹,        ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹.

In some embodiments, o=2; p=2 or 3; and

each R⁶ is independently selected from C₁-C₆ alkyl, C₃-C₇ cycloalkyl,C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halo, CN, C₆-C₁₀ aryl,5- to 10-membered heteroaryl, CO—C₁-C₆ alkyl; CONR⁸R⁹, and 4- to6-membered heterocycloalkyl,wherein the C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₇ cycloalkyl and 4- to6-membered heterocycloalkyl is optionally substituted with one or moresubstituents each independently selected from hydroxy, halo, CN, oxo,C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, CONR⁸R⁹, 4- to6-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl,OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO (5- to 10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl), NHCOC₁-C₆ alkyl, NHCOC₆-C₁₀ aryl,NHCO (5- to 10-membered heteroaryl), NHCO (4- to 6-memberedheterocycloalkyl), and NHCOC₂-C₆ alkynyl;

-   -   wherein each R⁷ is independently selected from C₁-C₆ alkyl,        C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halo, CN,        COC₁-C₆ alkyl, CO₂C₁-C₆ alkyl, CO₂C₃-C₆ cycloalkyl, OCOC₁-C₆        alkyl, OCOC₆-C₁₀ aryl, OCO (5- to 10-membered heteroaryl), OCO        (3- to 7-membered heterocycloalkyl), C₆-C₁₀ aryl, 5- to        10-membered heteroaryl, CONR⁸R⁹, SF₅, S(O₂)C₁-C₆ alkyl, C₃-C₇        cycloalkyl and 4- to 6-membered heterocycloalkyl, wherein the        C₁-C₆ alkyl is optionally substituted with one to two C₁-C₆        alkoxy;        or at least one pair of R⁶ and R⁷ on adjacent atoms, taken        together with the atoms connecting them, independently form at        least one C₄-C₇ (e.g., C₄-C₆) carbocyclic ring (e.g., aliphatic        carbocyclic ring) or at least one 5-to-7-membered (e.g.,        5-to-6-membered) heterocyclic ring containing 1 or 2 heteroatoms        independently selected from O, N, and S, wherein the carbocyclic        ring or heterocyclic ring is optionally independently        substituted with one or more substituents independently selected        from hydroxy, hydroxymethyl, halo, oxo, C₁-C₆ alkyl, C₁-C₆        alkoxy, NR⁸R⁹, CH₂NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and        CONR⁸R⁹.

In some embodiments, o=1 or 2; p=1, 2, or 3; and

R⁶ and R⁷ are each independently selected from C₁-C₆ alkyl, C₁-C₆alkoxy, halo, CN, NO₂, COC₁-C₆ alkyl, CO₂C₁-C₆ alkyl, C₆-C₁₀ aryl, 5- to10-membered heteroaryl, CONR⁸R⁹, and 3- to 7-membered heterocycloalkyl,wherein the C₁-C₆ alkyl and 3- to 7-membered heterocycloalkyl isoptionally substituted with one or more substituents each independentlyselected from hydroxy or oxo,or at least one pair of R⁶ and R⁷ on adjacent atoms, taken together withthe atoms connecting them, independently form at least one C₄-C₈carbocyclic ring, wherein the carbocyclic ring is optionallyindependently substituted with one or more hydroxy or oxo.

In some embodiments, o=1 or 2; p=1, 2, or 3; and

R⁶ and R⁷ are each independently selected from C₁-C₆ alkyl, C₁-C₆alkoxy, halo, CN, NO₂, COC₁-C₆ alkyl, CO₂C₁-C₆ alkyl, C₆-C₁₀ aryl, 5- to10-membered heteroaryl, CONR⁸R⁹, and 3- to 7-membered heterocycloalkyl,wherein the C₁-C₆ alkyl and 3- to 7-membered heterocycloalkyl isoptionally substituted with one or more substituents each independentlyselected from hydroxy or oxo.

In some embodiments, o=1 or 2; p=1, 2, or 3; and

one R⁶ and one R⁷ are on adjacent atoms, and taken together with theatoms connecting them, form a C₄-C₈ carbocyclic ring or a 5- to8-membered heterocyclic ring containing 1 or 2 heteroatoms independentlyselected from O, N, and S, wherein the carbocyclic ring or heterocyclicring is optionally independently substituted with one or moresubstituents independently selected from hydroxy, halo, oxo, C₁-C₆alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, andCONR⁸R⁹.

In some embodiments, o=1 or 2; p=1, 2, or 3; and

one R⁶ and one R⁷ are on adjacent atoms, and taken together with theatoms connecting them, form a C₆ carbocyclic ring or a 5-to-6-memberedheterocyclic ring containing 1 or 2 heteroatoms independently selectedfrom O, N, and S, wherein the carbocyclic ring or heterocyclic ring isoptionally independently substituted with one or more substituentsindependently selected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₁-C₆alkoxy, NR⁸R⁹, NR¹⁰ COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹.

In some embodiments, o=1 or 2; p=1, 2, or 3; and

one R⁶ and one R⁷ are on adjacent atoms, and taken together with theatoms connecting them, form a C₄-C₈ carbocyclic ring or a 5- to8-membered heterocyclic ring containing 1 or 2 heteroatoms independentlyselected from O, N, and S, wherein the carbocyclic ring or heterocyclicring is unsubstituted.

In some embodiments, o=2; p=2 or 3; and

two pairs, each of one R⁶ and one R⁷, are on adjacent atoms, and eachpair of one R⁶ and one R⁷ taken together with the atoms connecting themindependently form a C₄-C₈ carbocyclic ring or a 5- to 8-memberedheterocyclic ring containing 1 or 2 heteroatoms independently selectedfrom O, N, and S, wherein each carbocyclic ring or heterocyclic ring isoptionally independently substituted with one or more substituentsindependently selected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₁-C₆alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹.

In some embodiments, o=2; p=2 or 3; and

two pairs, each of one R⁶ and one R⁷, are on adjacent atoms, and eachpair of one R⁶ and one R⁷ taken together with the atoms connecting themindependently form a C₆ carbocyclic ring or a 5-to-6-memberedheterocyclic ring containing 1 or 2 heteroatoms independently selectedfrom O, N, and S, wherein the carbocyclic ring or heterocyclic ring isoptionally independently substituted with one or more substituentsindependently selected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₁-C₆alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹.

In some embodiments, o=2; p=2 or 3; and

two pairs, each of one R⁶ and one R⁷, are on adjacent atoms, and eachpair of one R⁶ and one R⁷ taken together with the atoms connecting themindependently form a C₅ carbocyclic ring, wherein the carbocyclic ringis optionally independently substituted with one or more substituentsindependently selected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₁-C₆alkoxy, NR⁸R⁹, ═NR¹⁰ COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹.

In some embodiments, o=2; p=2 or 3; and

two pairs, each of one R⁶ and one R⁷, are on adjacent atoms, and eachpair of one R⁶ and one R⁷ taken together with the atoms connecting themindependently form a C₄ carbocyclic ring, wherein the carbocyclic ringis optionally independently substituted with one or more substituentsindependently selected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₁-C₆alkoxy, NR⁸R⁹, ═NR¹⁰ COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹.

In some embodiments, o=2; p=2 or 3; and

two pairs, each of one R⁶ and one R⁷, are on adjacent atoms, one pair ofone R⁶ and one R⁷ taken together with the atoms connecting themindependently form a C₄ carbocyclic ring, and the other pair of one R⁶and one R⁷ taken together with the atoms connecting them independentlyform a C₅ carbocyclic ring, wherein each of C₄ and C₅ carbocyclic ringis optionally independently substituted with one or more substituentsindependently selected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₁-C₆alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹.

In some embodiments, o=2; p=2 or 3; and

two pairs, each of one R⁶ and one R⁷, are on adjacent atoms, one pair ofone R⁶ and one R⁷ taken together with the atoms connecting themindependently form a C₅ carbocyclic ring, and the other pair of one R⁶and one R⁷ taken together with the atoms connecting them independentlyform a 5- to 8-membered heterocyclic ring containing 1 or 2 heteroatomsindependently selected from O, N, and S (e.g., a 5-memberedheteorocyclic ring, e.g., 5-membered heterocyclic ring containing 1heteroatom), wherein each of carbocyclic and heterocyclic ring isoptionally independently substituted with one or more substituentsindependently selected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₁-C₆alkoxy, NR⁸R⁹, ═NR¹⁰ COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹.

In some embodiments, o=2; p=2 or 3; and

two pairs, each of one R⁶ and one R⁷, are on adjacent atoms, and eachpair of one R⁶ and one R⁷ taken together with the atoms connecting themindependently form a C₄-C₈ carbocyclic ring or a 5- to 8-memberedheterocyclic ring containing 1 or 2 heteroatoms independently selectedfrom O, N, and S, wherein the carbocyclic ring or heterocyclic ring isunsubstituted.

Particular Embodiments Wherein o=1; p=0:

In some embodiments, R⁶ is C₁-C₆ alkyl.

In some embodiments, R⁶ is isopropyl.

In some embodiments, R⁶ is ethyl.

In some embodiments, R⁶ is methyl.

In some embodiments, R⁶ is C₁-C₆ alkyl substituted with one or morehalo.

In some embodiments, R⁶ is trifluoromethyl.

In some embodiments, R⁶ is trifluoromethoxy.

In some embodiments, R⁶ is C₃-C₇ cycloalkyl.

In some embodiments, R⁶ is cyclopropyl.

In some embodiments, R⁶ is halo.

In some embodiments, R⁶ is chloro.

In some embodiments, R⁶ is fluoro.

In some embodiments, R⁶ is cyano.

In some embodiments, R⁶ is attached to a carbon of an aryl ring B.

In some embodiments, R⁶ is attached to a carbon of a heteroaryl ring B.

In some embodiments, R⁶ is attached to a nitrogen of a heteroaryl ringB.

Particular Embodiments Wherein o=1 or 2; p=1, 2, or 3:

In some embodiments, at least one R⁶ is C₁-C₆ alkyl, and at least one R⁷is C₁-C₆ alkyl optionally substituted with one or more halo.

In some embodiments, at least one R⁶ is C₁-C₆ alkyl and at least one R⁷is C₁-C₆ alkyl.

In some embodiments, at least one R⁶ is isopropyl and at least one R⁷ ismethyl.

In some embodiments, at least one R⁶ is isopropyl and at least one R⁷ isisopropyl.

In some embodiments, o=1; p=1; R⁶ is isopropyl; and R⁷ is isopropyl.

In some embodiments, at least one R⁶ is C₁-C₆ alkyl, and at least one R⁷is C₁-C₆ alkyl substituted with one or more halo.

In some embodiments, at least one R⁶ is isopropyl and at least one R⁷ istrifluoromethyl.

In some embodiments, at least one R⁶ is C₁-C₆ alkyl, and at least one R⁷is C₃-C₇ cycloalkyl.

In some embodiments, at least one R⁶ is isopropyl and at least one R⁷ iscyclopropyl.

In some embodiments, o=1; p=1; R⁶ is isopropyl; and R⁷ is cyclopropyl.

In some embodiments, at least one R⁶ is C₁-C₆ alkyl, and at least one R⁷is halo.

In some embodiments, at least one R⁶ is isopropyl and at least one R⁷ ishalo.

In some embodiments, at least one R⁶ is isopropyl and at least one R⁷ ischloro.

In some embodiments, at least one R⁶ is isopropyl and at least one R⁷ isfluoro.

In some embodiments, o=1; p=1; R⁶ is isopropyl; and R⁷ is chloro.

In some embodiments, o=2; p=1; at least one R⁶ is isopropyl; and R⁷ ischloro.

In some embodiments, o=1; p=1; R⁶ is isopropyl; and R⁷ is fluoro.

In some embodiments, o=2; p=1; at least one R⁶ is isopropyl; and R⁷ isfluoro.

In some embodiments, o=2; p=2; at least one R⁶ is isopropyl; and atleast one R⁷ is fluoro.

In some embodiments, o=2; p=2; at least one R⁶ is isopropyl; one R⁷ isfluoro; and the other R⁷ is cyano.

In some embodiments, o=2; p=3; at least one R⁶ is isopropyl; two R⁷ arefluoro; and one R⁷ is chloro.

In some embodiments, o=2; p=1; at least one R⁶ is ethyl; and R⁷ isfluoro.

In some embodiments, o=2; p=1; one R⁶ is isopropyl; the other R⁶ istrifluoromethyl; and R⁷ is chloro.

In some embodiments, at least one R⁶ is C₁-C₆ alkyl, and at least one R⁷is cyano.

In some embodiments, at least one R⁶ is isopropyl and at least one R⁷ iscyano.

In some embodiments, o=1; p=1; R⁶ is isopropyl; and R⁷ is cyano.

In some embodiments, o=2; p=1; at least one R⁶ is isopropyl; and R⁷ iscyano.

In some embodiments, at least one R⁶ is C₃-C₇ cycloalkyl, and at leastone R⁷ is C₃-C₇ cycloalkyl.

In some embodiments, at least one R⁶ is cyclopropyl, and at least one R⁷is cyclopropyl.

In some embodiments, at least one R⁶ is C₃-C₇ cycloalkyl, and at leastone R⁷ is halo.

In some embodiments, at least one R⁶ is cyclopropyl and at least one R⁷is halo.

In some embodiments, at least one R⁶ is cyclopropyl and at least one R⁷is chloro.

In some embodiments, at least one R⁶ is cyclopropyl and at least one R⁷is fluoro.

In some embodiments, o=1; p=1; R⁶ is cyclopropyl; and R⁷ is chloro.

In some embodiments, o=1; p=1; R⁶ is cyclopropyl; and R⁷ is fluoro.

In some embodiments, at least one R⁶ is C₁-C₆ alkyl, and at least one R⁷is C₁-C₆ alkoxy optionally substituted with one or more halo.

In some embodiments, at least one R⁶ is isopropyl, and at least one R⁷is C₁-C₆ alkoxy.

In some embodiments, at least one R⁶ is isopropyl, and at least one R⁷is methoxy.

In some embodiments, o=1; p=1; R⁶ is isopropyl, and R⁷ is methoxy.

In some embodiments, o=2; p=1; at least one R⁶ is isopropyl, and R⁷ ismethoxy.

In some embodiments, at least one R⁶ is C₁-C₆ alkyl, and at least one R⁷is C₁-C₆ alkoxy substituted with one or more halo.

In some embodiments, at least one R⁶ is isopropyl, and at least one R⁷is trifluoromethoxy.

In some embodiments, at least one R⁶ is isopropyl, and at least one R⁷is difluoromethoxy.

In some embodiments, at least one R⁶ is halo, and at least one R⁷ isC₁-C₆ haloalkyl optionally substituted with hydroxy.

In some embodiments, o=1; p=1; R⁶ is chloro, and R⁷ is trifluoromethyl.

In some embodiments, at least one R⁶ is halo, and at least one R⁷ isC₁-C₆ haloalkoxy.

In some embodiments, at least one R⁶ is chloro, and at least one R⁷ istrifluoromethoxy.

In some embodiments, o=1; p=1; R⁶ is chloro, and R⁷ is trifluoromethoxy.

In some embodiments, at least one R⁶ is C₁-C₆ alkoxy; and at least oneR⁷ is halo.

In some embodiments, o=1; p=2; R⁶ is C₁-C₆ alkoxy; and at least one R⁷is chloro.

In some embodiments, at least one R⁷ is C₁-C₆ alkyl, and at least one R⁶is C₁-C₆ alkyl optionally substituted with one or more halo.

In some embodiments, at least one R⁷ is isopropyl and at least one R⁶ ismethyl.

In some embodiments, at least one R⁷ is C₁-C₆ alkyl, and at least one R⁶is C₁-C₆ alkyl substituted with one or more halo.

In some embodiments, at least one R⁷ is isopropyl and at least one R⁶ istrifluoromethyl.

In some embodiments, at least one R⁷ is C₁-C₆ alkyl, and at least one R⁶is C₃-C₇ cycloalkyl.

In some embodiments, at least one R⁷ is isopropyl and at least one R⁶ iscyclopropyl.

In some embodiments, o=1; p=1; R⁷ is isopropyl; and R⁶ is cyclopropyl.

In some embodiments, at least one R⁷ is C₁-C₆ alkyl, and at least one R⁶is halo.

In some embodiments, at least one R⁷ is isopropyl and at least one R⁶ ishalo.

In some embodiments, at least one R⁷ is isopropyl and at least one R⁶ ischloro.

In some embodiments, at least one R⁷ is isopropyl and at least one R⁶ isfluoro.

In some embodiments, o=1; p=1; R⁷ is isopropyl; and R⁶ is chloro.

In some embodiments, o=2; p=1; R⁷ is isopropyl; and at least one R⁶ ischloro.

In some embodiments, o=1; p=1; R⁷ is isopropyl; and R⁶ is fluoro.

In some embodiments, o=2; p=1; R⁷ is isopropyl; and at least one R⁶ isfluoro.

In some embodiments, o=2; p=2; R⁷ is isopropyl; and at least one R⁶ isfluoro.

In some embodiments, o=2; p=2; at least one R⁷ is isopropyl; one R⁶ isfluoro; and the other R⁶ is cyano.

In some embodiments, o=2; p=1; R⁷ is ethyl; and at least one R⁶ isfluoro.

In some embodiments, o=1; p=2; one R⁷ is isopropyl; the other R⁷ istrifluoromethyl; and R⁶ is chloro.

In some embodiments, at least one R⁷ is C₁-C₆ alkyl, and at least one R⁶is cyano.

In some embodiments, at least one R⁷ is isopropyl and at least one R⁶ iscyano.

In some embodiments, o=1; p=1; R⁷ is isopropyl; and R⁶ is cyano.

In some embodiments, o=2; p=1; R⁷ is isopropyl; and at least one R⁶ iscyano.

In some embodiments, at least one R⁷ is C₃-C₇ cycloalkyl, and at leastone R⁶ is C₃-C₇ cycloalkyl.

In some embodiments, at least one R⁷ is cyclopropyl, and at least one R⁶is cyclopropyl.

In some embodiments, at least one R⁷ is C₃-C₇ cycloalkyl, and at leastone R⁶ is halo.

In some embodiments, at least one R⁷ is cyclopropyl and at least one R⁶is halo.

In some embodiments, at least one R⁷ is cyclopropyl and at least one R⁶is chloro.

In some embodiments, at least one R⁷ is cyclopropyl and at least one R⁶is fluoro.

In some embodiments, o=1; p=1; R⁷ is cyclopropyl; and R⁶ is chloro.

In some embodiments, o=1; p=1; R⁷ is cyclopropyl; and R⁶ is fluoro.

In some embodiments, at least one R⁷ is C₁-C₆ alkyl, and at least one R⁶is C₁-C₆ alkoxy optionally substituted with one or more halo.

In some embodiments, at least one R⁷ is isopropyl, and at least one R⁶is C₁-C₆ alkoxy.

In some embodiments, at least one R⁷ is isopropyl, and at least one R⁶is methoxy.

In some embodiments, o=1; p=1; R⁷ is isopropyl, and R⁶ is methoxy.

In some embodiments, o=2; p=1; R⁷ is isopropyl, and at least one R⁶ ismethoxy.

In some embodiments, at least one R⁷ is C₁-C₆ alkyl, and at least one R⁶is C₁-C₆ alkoxy substituted with one or more halo.

In some embodiments, at least one R⁷ is isopropyl, and at least one R⁶is trifluoromethoxy.

In some embodiments, at least one R⁷ is halo, and at least one R⁶ isC₁-C₆ haloalkyl optionally substituted with one or more hydroxy.

In some embodiments, o=1; p=1; R⁷ is chloro, and R⁶ is trifluoromethyl.

In some embodiments, at least one R⁷ is halo, and at least one R⁶ isC₁-C₆ haloalkoxy.

In some embodiments, at least one R⁷ is chloro, and at least one R⁶ istrifluoromethoxy.

In some embodiments, o=1; p=1; R⁷ is chloro, and R⁶ is trifluoromethoxy.

In some embodiments, at least one R⁷ is C₁-C₆ alkoxy; and at least oneR⁶ is halo.

In some embodiments, o=1; p=2; at least one R⁷ is C₁-C₆ alkoxy; and R⁶is chloro.

In some embodiments, R⁶ and R⁷ are each attached to a carbon of an arylring B.

In some embodiments, R⁶ and R⁷ are each attached to a carbon of aheteroaryl ring B.

In some embodiments, R⁶ is attached to a carbon and R⁷ is attached to anitrogen of a heteroaryl ring B.

In some embodiments, R⁷ is attached to a carbon and R⁶ is attached to anitrogen of a heteroaryl ring B.

In some embodiments, one R⁶ and one R⁷ are on adjacent atoms, and takentogether with the atoms connecting them, form a C₅ carbocyclic ringoptionally substituted with one or more substituents independentlyselected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹,═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹.

In some embodiments, R⁶ and R⁷ are on adjacent atoms, and taken togetherwith the atoms connecting them, form a C₅ aliphatic carbocyclic ring.

In some embodiments, R⁶ and R⁷ are on adjacent atoms, and taken togetherwith the atoms connecting them, form a C₆ carbocyclic ring optionallysubstituted with one or more substituents independently selected fromhydroxy, halo, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰ COOC₁-C₆alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹.

In some embodiments, R⁶ and R⁷ are on adjacent atoms, and taken togetherwith the atoms connecting them, form a C₆ aliphatic carbocyclic ring.

In some embodiments, R⁶ and R⁷ are on adjacent atoms, and taken togetherwith the atoms connecting them, form a C₆ aromatic carbocyclic ring.

In some embodiments, R⁶ and R⁷ are on adjacent atoms, and taken togetherwith the atoms connecting them, form a 5-membered heterocyclic ringcontaining 1 or 2 heteroatoms independently selected from O, N, and S,optionally substituted with one or more substituents independentlyselected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹,═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹.

In some embodiments, R⁶ and R⁷ are on adjacent atoms, and taken togetherwith the atoms connecting them, form a 5-membered aliphatic heterocyclicring containing 1 or 2 heteroatoms independently selected from O, N, andS.

In some embodiments, R⁶ and R⁷ are on adjacent atoms, and taken togetherwith the atoms connecting them, form a 5-membered heteroaromatic ringcontaining 1 or 2 heteroatoms independently selected from O, N, and S.

In some embodiments, R⁶ and R⁷ are on adjacent atoms, and taken togetherwith the atoms connecting them, form a 6-membered heterocyclic ringcontaining 1 or 2 heteroatoms independently selected from O, N, and S,optionally substituted with one or more substituents independentlyselected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹,NR¹⁰. COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹.

In some embodiments, R⁶ and R⁷ are on adjacent atoms, and taken togetherwith the atoms connecting them, form a 6-membered aliphatic heterocyclicring containing 1 or 2 heteroatoms independently selected from O, N, andS.

In some embodiments, R⁶ and R⁷ are on adjacent atoms, and taken togetherwith the atoms connecting them, form a 6-membered heteroaromatic ringcontaining 1 or 2 heteroatoms independently selected from O, N, and S.

In some embodiments, one R⁶ and one R⁷ are on adjacent atoms, and takentogether with the atoms connecting them, form a C₄-C₈ carbocyclic ringor a 5- to 8-membered heterocyclic ring containing 1 or 2 heteroatomsindependently selected from O, N, and S, wherein the ring is fused tothe B ring at the 2- and 3-positions relative to the bond connecting theB ring to the NH(CO) group.

In some embodiments, o=1; p=2; and one pair of one R⁶ and one R⁷, are onadjacent atoms; and said pair of one R⁶ and one R⁷ taken together withthe atoms connecting them form form a C₄-C₈ carbocyclic ring or a 5- to8-membered heterocyclic ring containing 1 or 2 heteroatoms independentlyselected from O, N, and S,

wherein the ring is fused to the B ring at the 2- and 3-positionsrelative to the bond connecting the B ring to the NR³(CO) group.

In some embodiments, o=1; p=2; and

one pair of one R⁶ and one R⁷, are on adjacent atoms; and said pair ofone R⁶ and one R⁷ taken together with the atoms connecting them formform a C₄-C₈ carbocyclic ring optionally independently substituted withone or more substituents independently selected from hydroxy, halo, oxo,C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰ COOC₁-C₆ alkyl, C₆-C₁₀ aryl, andCONR⁸R⁹.

In some embodiments, o=1; p=2; and

one pair of one R⁶ and one R⁷, are on adjacent atoms; and said pair ofone R⁶ and one R⁷ taken together with the atoms connecting them formform a C₅ carbocyclic ring optionally independently substituted with oneor more substituents independently selected from hydroxy, halo, oxo,C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰ COOC₁-C₆ alkyl, C₆-C₁₀ aryl, andCONR⁸R⁹.

In some embodiments, o=1; p=2; and

one pair of one R⁶ and one R⁷, are on adjacent atoms; and said pair ofone R⁶ and one R⁷ taken together with the atoms connecting them formform a C₅ aliphatic carbocyclic ring.

In some embodiments, o=2; p=2; and

one pair of one R⁶ and one R⁷, are on adjacent atoms; and said pair ofone R⁶ and one R⁷ taken together with the atoms connecting them formform a C₄-C₈ carbocyclic ring optionally independently substituted withone or more substituents independently selected from hydroxy, halo, oxo,C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰ COOC₁-C₆ alkyl, C₆-C₁₀ aryl, andCONR⁸R⁹.

In some embodiments, o=2; p=2; and

one pair of one R⁶ and one R⁷, are on adjacent atoms; and said pair ofone R⁶ and one R⁷ taken together with the atoms connecting them formform a C₅ carbocyclic ring optionally independently substituted with oneor more substituents independently selected from hydroxy, halo, oxo,C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl,and CONR⁸R⁹.

In some embodiments, o=1; p=2; and

one pair of one R⁶ and one R⁷, are on adjacent atoms; and said pair ofone R⁶ and one R⁷ taken together with the atoms connecting them formform a C₅ aliphatic carbocyclic ring.

In some embodiments, o=2; p=2 or 3; and

two pairs, each of one R⁶ and one R⁷, are on adjacent atoms; one pair ofone R⁶ and one R⁷ taken together with the atoms connecting them form aC₄ carbocyclic ring optionally independently substituted with one ormore substituents independently selected from hydroxy, halo, oxo, C₁-C₆alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, andCONR⁸R⁹; and the other pair of one R⁶ and one R⁷ taken together with theatoms connecting them form a C₅ carbocyclic ring optionallyindependently substituted with one or more substituents independentlyselected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹,═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹.

In some embodiments, o=2; p=2 or 3; and

two pairs, each of one R⁶ and one R⁷, are on adjacent atoms; one pair ofone R⁶ and one R⁷ taken together with the atoms connecting them form aC₄ aliphatic carbocyclic ring and the other pair of one R⁶ and one R⁷taken together with the atoms connecting them form a C₅ aliphaticcarbocyclic ring.

In some embodiments, o=2; p=2 or 3; and

two pairs, each of one R⁶ and one R⁷, are on adjacent atoms, and eachpair of one R⁶ and one R⁷ taken together with the atoms connecting themform a C₅ carbocyclic ring optionally independently substituted with oneor more substituents independently selected from hydroxy, halo, oxo,C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl,and CONR⁸R⁹.

In some embodiments, o=2; p=2 or 3; and

two pairs, each of one R⁶ and one R⁷, are on adjacent atoms, and eachpair of one R⁶ and one R⁷ taken together with the atoms connecting themform a C₅ aliphatic carbocyclic ring.

In some embodiments, o=2; p=2 or 3; and

two pairs, each of one R⁶ and one R⁷, are on adjacent atoms, and eachpair of one R⁶ and one R⁷ taken together with the atoms connecting themform a C₆ carbocyclic ring optionally independently substituted with oneor more substituents independently selected from hydroxy, halo, oxo,C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰ COOC₁-C₆ alkyl, C₆-C₁₀ aryl, andCONR⁸R⁹.

In some embodiments, o=2; p=2 or 3; and

two pairs, each of one R⁶ and one R⁷, are on adjacent atoms, and eachpair of one R⁶ and one R⁷ taken together with the atoms connecting themform a C₆ aliphatic carbocyclic ring.

In some embodiments, o=2; p=2 or 3; and

two pairs, each of one R⁶ and one R⁷, are on adjacent atoms, and eachpair of one R⁶ and one R⁷ taken together with the atoms connecting themform a C₆ aromatic carbocyclic ring.

In some embodiments, o=2; p=2 or 3; and

two pairs, each of one R⁶ and one R⁷, are on adjacent atoms, and eachpair of one R⁶ and one R⁷ taken together with the atoms connecting themform a 5-membered heterocyclic ring containing 1 or 2 heteroatomsindependently selected from O, N, and S, optionally substituted with oneor more substituents independently selected from hydroxy, halo, oxo,C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl,and CONR⁸R⁹.

In some embodiments, o=2; p=2 or 3; and

two pairs, each of one R⁶ and one R⁷, are on adjacent atoms, and eachpair of one R⁶ and one R⁷ taken together with the atoms connecting themform a 5-membered aliphatic heterocyclic ring containing 1 or 2heteroatoms independently selected from O, N, and S.

In some embodiments, o=2; p=2 or 3; and

two pairs, each of one R⁶ and one R⁷, are on adjacent atoms, and eachpair of one R⁶ and one R⁷ taken together with the atoms connecting themform a 5-membered heteroaromatic ring containing 1 or 2 heteroatomsindependently selected from O, N, and S.

In some embodiments, o=2; p=2 or 3; and

two pairs, each of one R⁶ and one R⁷, are on adjacent atoms, and eachpair of one R⁶ and one R⁷ taken together with the atoms connecting themform a 6-membered heterocyclic ring containing 1 or 2 heteroatomsindependently selected from O, N, and S, optionally substituted with oneor more substituents independently selected from hydroxy, halo, oxo,C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl,and CONR⁸R⁹.

In some embodiments, o=2; p=2 or 3; and

two pairs, each of one R⁶ and one R⁷, are on adjacent atoms, and eachpair of one R⁶ and one R⁷ taken together with the atoms connecting themform a 6-membered aliphatic heterocyclic ring containing 1 or 2heteroatoms independently selected from O, N, and S.

In some embodiments, o=2; p=2 or 3; and

two pairs, each of one R⁶ and one R⁷, are on adjacent atoms, and eachpair of one R⁶ and one R⁷ taken together with the atoms connecting themform a 6-membered heteroaromatic ring containing 1 or 2 heteroatomsindependently selected from O, N, and S.

In some embodiments, o=2; p=2 or 3; and

two pairs, each of one R⁶ and one R⁷, are on adjacent atoms; one pair ofone R⁶ and one R⁷ taken together with the atoms connecting them form aC₄-8 carbocyclic ring optionally independently substituted with one ormore substituents independently selected from hydroxy, halo, oxo, C₁-C₆alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, andCONR⁸R⁹; and the other pair of one R⁶ and one R⁷ taken together with theatoms connecting them form a 5- to 8-membered heterocyclic ringcontaining 1 or 2 heteroatoms independently selected from O, N, and S,optionally substituted with one or more substituents independentlyselected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹,═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹.

In some embodiments, o=2; p=2 or 3; and

two pairs, each of one R⁶ and one R⁷, are on adjacent atoms; one pair ofone R⁶ and one R⁷ taken together with the atoms connecting them form aC₅ aliphatic carbocyclic ring and the other pair of one R⁶ and one R⁷taken together with the atoms connecting them form a 5-memberedaliphatic heterocyclic ring containing 1 or 2 heteroatoms independentlyselected from O, N, and S.

In some embodiments, o=2; p=2 or 3; and

two pairs, each of one R⁶ and one R⁷, are on adjacent atoms; one pair ofone R⁶ and one R⁷ taken together with the atoms connecting them form aC₅ carbocyclic ring optionally independently substituted with one ormore substituents independently selected from hydroxy, halo, oxo, C₁-C₆alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, andCONR⁸R⁹; and the other pair of one R⁶ and one R⁷ taken together with theatoms connecting them form a 6-membered heterocyclic ring containing 1or 2 heteroatoms independently selected from O, N, and S, optionallysubstituted with one or more substituents independently selected fromhydroxy, halo, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹.

In some embodiments, o=2; p=2 or 3; and

two pairs, each of one R⁶ and one R⁷, are on adjacent atoms; one pair ofone R⁶ and one R⁷ taken together with the atoms connecting them form aC₅ aliphatic carbocyclic ring and the other pair of one R⁶ and one R⁷taken together with the atoms connecting them form a 5-memberedaliphatic heterocyclic ring containing 1 or 2 heteroatoms independentlyselected from O, N, and S.

In some embodiments, o=2; p=2 or 3; and

two pairs, each of one R⁶ and one R⁷, are on adjacent atoms, and eachpair of one R⁶ and one R⁷ taken together with the atoms connecting themindependently form a C₄-C₈ carbocyclic ring or a 5- to 8-memberedheterocyclic ring containing 1 or 2 heteroatoms independently selectedfrom O, N, and S, wherein one of the two rings is fused to the B ring atthe 2- and 3-positions relative to the bond connecting the B ring to theNR³(CO) group, and the other of the two rings is fused to the B ring atthe 5- and 6-positions relative to the bond connecting the B ring to theNH(CO) group.

In some embodiments, o=2; p=2 or 3; and

two pairs, each of one R⁶ and one R⁷, are on adjacent atoms, and eachpair of one R⁶ and one R⁷ taken together with the atoms connecting themindependently form a C₄-C₈ carbocyclic ring or a 5- to 8-memberedheterocyclic ring containing 1 or 2 heteroatoms independently selectedfrom O, N, and S,wherein one of the two rings is fused to the B ring at the 2- and3-positions relative to the bond connecting the B ring to the NR³(CO)group, and the other of the two rings is fused to the B ring at the 4-and 5-positions relative to the bond connecting the B ring to the NH(CO)group.

In some embodiments, o=2; p=2; and

two pairs, each of one R⁶ and one R⁷, are on adjacent atoms, and eachpair of one R⁶ and one R⁷ taken together with the atoms connecting themform a C₅ aliphatic carbocyclic ring.

In some embodiments, o=2; p=2; and

two pairs, each of one R⁶ and one R⁷, are on adjacent atoms, one pair ofone R⁶ and one R⁷ taken together with the atoms connecting them form aC₄ aliphatic carbocyclic ring, and the other pair of one R⁶ and one R⁷taken together with the atoms connecting them form a C₅ aliphaticcarbocyclic ring.

In some embodiments, o=2; p=2; and

two pairs, each of one R⁶ and one R⁷, are on adjacent atoms, and eachpair of one R⁶ and one R⁷ taken together with the atoms connecting themform a C₄ aliphatic carbocyclic ring.

In some embodiments, o=2; p=2; and

two pairs, each of one R⁶ and one R⁷, are on adjacent atoms, one pair ofone R⁶ and one R⁷ taken together with the atoms connecting them form aC₅ aliphatic carbocyclic ring, and the other pair of one R⁶ and one R⁷taken together with the atoms connecting them form a 5-memberedheterocyclic ring containing 1 or 2 heteroatoms independently selectedfrom O, N, and S.

In some embodiments, o=2; p=3; and

two pairs, each of one R⁶ and one R⁷, are on adjacent atoms, and eachpair of one R⁶ and one R⁷ taken together with the atoms connecting themform a C₅ aliphatic carbocyclic ring; and one R⁷ is halo (e.g., Cl orF).

In some embodiments, o=2; p=3; and

two pairs, each of one R⁶ and one R⁷, are on adjacent atoms, and eachpair of one R⁶ and one R⁷ taken together with the atoms connecting themform a C₅ aliphatic carbocyclic ring; and one R⁷ is CN.

In some embodiments, one R⁷ is pyrazolyl and is para to the bondconnecting the B ring to the NH(CO) group of Formula AA.

In some embodiments, one R⁷ is 3-pyrazolyl and is para to the bondconnecting the B ring to the NH(CO) group of Formula AA.

In some embodiments, one R⁷ is 4-pyrazolyl and is para to the bondconnecting the B ring to the NH(CO) group of Formula AA.

In some embodiments, one R⁷ is 5-pyrazolyl and is para to the bondconnecting the B ring to the NH(CO) group of Formula AA.

In some embodiments, one R⁷ is thiazolyl and is para to the bondconnecting the B ring to the NH(CO) group of Formula AA.

In some embodiments, one R⁷ is 4-thiazolyl and is para to the bondconnecting the B ring to the NH(CO) group of Formula AA.

In some embodiments, one R⁷ is 5-thiazolyl and is para to the bondconnecting the B ring to the NH(CO) group of Formula AA.

In some embodiments, one R⁷ is furyl and is para to the bond connectingthe B ring to the NH(CO) group of Formula AA.

In some embodiments, one R⁷ is 2-furyl and is para to the bondconnecting the B ring to the NH(CO) group of Formula AA.

In some embodiments, one R⁷ is thiophenyl and is para to the bondconnecting the B ring to the NH(CO) group of Formula AA.

In some embodiments, one R⁷ is 2-thiophenyl and is para to the bondconnecting the B ring to the NH(CO) group of Formula AA.

In some embodiments, one R⁷ is phenyl and is para to the bond connectingthe B ring to the NH(CO) group of Formula AA.

In some embodiments, one R⁷ is cycloalkenyl (e.g., cyclopentenyl, e.g.,1-cyclopentenyl) and is para to the bond connecting the B ring to theNR³(CO) group of Formula AA.

In some embodiments, one R⁷ is phenyl optionally substituted with one ormore C₁-C₆ alkyl (e.g., methyl or propyl, e.g., 2-propyl) optionallysubstituted with one or more hydroxyl, NR⁸R⁹ (e.g., dimethylamino), orC₆-C₁₀ aryl (e.g., phenyl, naphthyl, or methylenedioxyphenyl and is parato the bond connecting the B ring to the NH(CO) group of Formula AA.

In some embodiments, one R⁷ is phenyl optionally substituted with one ormore C₁-C₆ alkoxy (e.g., methoxy) optionally substituted with one ormore hydroxyl, NR⁸R⁹ (e.g., dimethylamino), or C₆-C₁₀ aryl (e.g.,phenyl, naphthyl, or methylenedioxyphenyl and is para to the bondconnecting the B ring to the NH(CO) group of Formula AA.

In some embodiments, one R⁷ is phenyl optionally substituted with one ormore C₆-C₁₀ aryloxy (e.g., phenoxy) and is para to the bond connectingthe B ring to the NH(CO) group of Formula AA.

In some embodiments, one R⁷ is phenyl optionally substituted with one ormore CN and is para to the bond connecting the B ring to the NH(CO)group of Formula AA.

In some embodiments, one R⁷ is phenyl optionally substituted with one ormore halo (e.g., F, Cl) and is para to the bond connecting the B ring tothe NH(CO) group of Formula AA and is para to the bond connecting the Bring to the NH(CO) group of Formula AA.

In some embodiments, one R⁷ is phenyl optionally substituted with one ormore COOC₁-C₆ alkyl (e.g., CO₂t-Bu) and is para to the bond connectingthe B ring to the NH(CO) group of Formula AA.

In some embodiments, one R⁷ is phenyl optionally substituted with one ormore S(O₂)C₁-C₆ alkyl (e.g., S(O₂)methyl) and is para to the bondconnecting the B ring to the NH(CO) group of Formula AA.

In some embodiments, one R⁷ is phenyl optionally substituted with one ormore 3- to 7-membered heterocycloalkyl (e.g., morpholinyl) and is parato the bond connecting the B ring to the NH(CO) group of Formula AA.

In some embodiments, one R⁷ is phenyl optionally substituted with one ormore CONR⁸R⁹ (e.g., unsubstituted amido) and is para to the bondconnecting the B ring to the NH(CO) group of Formula AA.

In some embodiments, one R⁷ is phenyl optionally substituted with one ormore C₁-C₆ alkyl (e.g., methyl or propyl, e.g., 2-propyl) and with oneor more halo (e.g., F, Cl) and is para to the bond connecting the B ringto the NH(CO) group of Formula AA and is para to the bond connecting theB ring to the NH(CO) group of Formula AA.

In some embodiments, R⁶ and R⁷ are each attached to a carbon of an arylring B.

In some embodiments, R⁶ and R⁷ are each attached to a carbon of aheteroaryl ring B.

In some embodiments, R⁶ is attached to a carbon and R⁷ is attached to anitrogen of a heteroaryl ring B.

In some embodiments, R⁷ is attached to a carbon and R⁶ is attached to anitrogen of a heteroaryl ring B.

In some embodiments of any of the formulae herein, each of R¹ and R² isindependently selected from the group consisting of C₁-C₆ alkyloptionally substituted with one or more hydroxy, halo, oxo, or C₁-C₆alkoxy; C₃-C₇ cycloalkyl optionally substituted with one or morehydroxy, halo, oxo, C₁-C₆ alkoxy, or C₁-C₆ alkyl; wherein the C₁-C₆alkoxy or C₁-C₆ alkyl is further optionally substituted with one tothree hydroxy, halo, NR⁸R⁹, or oxo; 3- to 7-membered heterocycloalkyloptionally substituted with one or more hydroxy, halo, oxo, or C₁-C₆alkyl wherein the C₁-C₆ alkoxy or C₁-C₆ alkyl is further optionallysubstituted with one to three hydroxy, halo, or oxo; C₁-C₆ haloalkyl;C₁-C₆ alkoxy; C₁-C₆ haloalkoxy; halo; CN; CO—C₁-C₆ alkyl; CO—C₆-C₁₀aryl; CO (5- to 10-membered heteroaryl); CO₂C₁-C₆ alkyl; CO₂C₃-C₈cycloalkyl; OCOC₁-C₆ alkyl; OCOC₆-C₁₀ aryl; OCO (5- to 10-memberedheteroaryl); OCO (3- to 7-membered heterocycloalkyl); C₆-C₁₀ aryl; 5- to10-membered heteroaryl; NH₂; NHC₁-C₆ alkyl; N(C₁-C₆ alkyl)₂; CONR⁸R⁹;SF₅; S(O₂)NR¹¹R¹²; S(O)C₁-C₆ alkyl; and S(O₂)C₁-C₆ alkyl.

In some embodiments of any of the formulae herein, R¹ is selected fromthe group consisting of 1-hydroxy-2-methylpropan-2-yl; methyl;isopropyl; 2-hydroxy-2-propyl; hydroxymethyl; 1-hydroxyethyl;2-hydroxyethyl; 1-hydroxy-2-propyl; 1-hydroxy-1-cyclopropyl;1-hydroxy-1-cyclobutyl; 1-hydroxy-1-cyclopentyl; 1-hydroxy-1-cyclohexyl;morpholinyl; 1,3-dioxolan-2-yl; COCH₃; COCH₂CH₃; 2-methoxy-2-propyl;fluoro; chloro; phenyl; pyridyl; pyrazolyl; S(O₂)CH₃, and S(O₂)NR¹¹R¹².

-   -   In some embodiments, R² is selected from the group consisting of        fluoro, chloro, cyano, methyl; methoxy; ethoxy; isopropyl;        1-hydroxy-2-methylpropan-2-yl; 2-hydroxy-2-propyl;        hydroxymethyl; 1-hydroxyethyl; 2-hydroxyethyl;        1-hydroxy-2-propyl; 1-hydroxy-1-cyclopropyl; COCH₃; COPh;        2-methoxy-2-propyl; S(O₂)CH₃, and S(O₂)NR¹¹R¹².    -   In some embodiments, the substituted ring B is

-   -    and each R⁶ is independently selected from the group consisting        of: C₁-C₆ alkyl, C₃-C₇ cycloalkyl, C₁-C₆ haloalkyl, C₁-C₆        alkoxy, C₁-C₆ haloalkoxy, halo, CN, C₆-C₁₀ aryl, 5- to        10-membered heteroaryl, CO—C₁-C₆ alkyl; CONR⁸R⁹, and 4- to        6-membered heterocycloalkyl, wherein the C₁-C₆ alkyl, C₁-C₆        haloalkyl, C₃-C₇ cycloalkyl and 4- to 6-membered        heterocycloalkyl is optionally substituted with one or more        substituents each independently selected from hydroxy, halo, CN,        oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl,        CONR⁸R⁹, 4- to 6-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to        10-membered heteroaryl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO (5-        to 10-membered heteroaryl), OCO (4- to 6-membered        heterocycloalkyl), NHCOC₁-C₆ alkyl, NHCOC₆-C₁₀ aryl, NHCO (5- to        10-membered heteroaryl), NHCO (4- to 6-membered        heterocycloalkyl), and NHCOC₂-C₆ alkynyl.    -   In some embodiments, the substituted ring B is

-   -    and each R⁶ is independently selected from the group consisting        of: C₁-C₆ alkyl, C₃-C₇ cycloalkyl, C₁-C₆ haloalkyl, C₁-C₆        alkoxy, C₁-C₆ haloalkoxy, wherein the C₁-C₆ alkyl, C₁-C₆        haloalkyl, and C₃-C₇ cycloalkyl is optionally substituted with        one or more substituents each independently selected from        hydroxy, halo, CN, or oxo.    -   In some embodiments, the substituted ring B is

-   -    wherein each R⁶ is independently selected from C₁-C₆ alkyl,        C₃-C₇ cycloalkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆        haloalkoxy, halo, CN, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl,        CO—C₁-C₆ alkyl; CONR⁸R⁹, and 4- to 6-membered heterocycloalkyl,        wherein the C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₇ cycloalkyl and        4- to 6-membered heterocycloalkyl is optionally substituted with        one or more substituents each independently selected from        hydroxy, halo, CN, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰,        COOC₁-C₆ alkyl, CONR⁸R⁹, 4- to 6-membered heterocycloalkyl,        C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆ alkyl,        OCOC₆-C₁₀ aryl, OCO (5- to 10-membered heteroaryl), OCO (4- to        6-membered heterocycloalkyl), NHCOC₁-C₆ alkyl, NHCOC₆-C₁₀ aryl,        NHCO (5- to 10-membered heteroaryl), NHCO (4- to 6-membered        heterocycloalkyl), and NHCOC₂-C₆ alkynyl;    -   wherein R⁷ is independently selected from C₁-C₆ alkyl, C₁-C₆        haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halo, CN, COC₁-C₆        alkyl, CO₂C₁-C₆ alkyl, CO₂C₃-C₆ cycloalkyl, OCOC₁-C₆ alkyl,        OCOC₆-C₁₀ aryl, OCO (5- to 10-membered heteroaryl), OCO (3- to        7-membered heterocycloalkyl), C₆-C₁₀ aryl, 5- to 10-membered        heteroaryl, CONR⁸R⁹, SF₅, S(O₂)C₁-C₆ alkyl, C₃-C₇ cycloalkyl and        4- to 6-membered heterocycloalkyl, wherein the C₁-C₆ alkyl is        optionally substituted with one to two C₁-C₆ alkoxy;        or R⁶ and R⁷, taken together with the atoms connecting them,        independently form C₄-C₇ carbocyclic ring or at least one        5-to-7-membered heterocyclic ring containing 1 or 2 heteroatoms        independently selected from O, N, and S, wherein the carbocyclic        ring or heterocyclic ring is optionally independently        substituted with one or more substituents independently selected        from hydroxy, halo, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹,        ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹.

In some embodiments, the substituted ring B is

wherein each R⁶ is independently selected from C₁-C₆ alkyl, C₃-C₇cycloalkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halo, CN,C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, CO—C₁-C₆ alkyl; CONR⁸R⁹, and4- to 6-membered heterocycloalkyl,wherein the C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₇ cycloalkyl and 4- to6-membered heterocycloalkyl is optionally substituted with one or moresubstituents each independently selected from hydroxy, halo, CN, oxo,C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, CONR⁸R⁹, 4- to6-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl,OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO (5- to 10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl), NHCOC₁-C₆ alkyl, NHCOC₆-C₁₀ aryl,NHCO (5- to 10-membered heteroaryl), NHCO (4- to 6-memberedheterocycloalkyl), and NHCOC₂-C₆ alkynyl;

-   -   wherein R⁷ is independently selected from C₁-C₆ alkyl, C₁-C₆        haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halo, CN, COC₁-C₆        alkyl, CO₂C₁-C₆ alkyl, CO₂C₃-C₆ cycloalkyl, OCOC₁-C₆ alkyl,        OCOC₆-C₁₀ aryl, OCO (5- to 10-membered heteroaryl), OCO (3- to        7-membered heterocycloalkyl), C₆-C₁₀ aryl, 5- to 10-membered        heteroaryl, CONR⁸R⁹, SF₅, S(O₂)C₁-C₆ alkyl, C₃-C₇ cycloalkyl and        4- to 6-membered heterocycloalkyl, wherein the C₁-C₆ alkyl is        optionally substituted with one to two C₁-C₆ alkoxy;        or R⁶ and R⁷, taken together with the atoms connecting them,        independently form C₄-C₇ carbocyclic ring or at least one        5-to-7-membered heterocyclic ring containing 1 or 2 heteroatoms        independently selected from O, N, and S, wherein the carbocyclic        ring or heterocyclic ring is optionally independently        substituted with one or more substituents independently selected        from hydroxy, halo, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹,        ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹.    -   In some embodiments, the substituted ring B is

wherein each R⁶ is independently selected from C₁-C₆ alkyl, C₃-C₇cycloalkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halo, CN,C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, CO—C₁-C₆ alkyl; CONR⁸R⁹, and4- to 6-membered heterocycloalkyl,wherein the C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₇ cycloalkyl and 4- to6-membered heterocycloalkyl is optionally substituted with one or moresubstituents each independently selected from hydroxy, halo, CN, oxo,C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, CONR⁸R⁹, 4- to6-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl,OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO (5- to 10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl), NHCOC₁-C₆ alkyl, NHCOC₆-C₁₀ aryl,NHCO (5- to 10-membered heteroaryl), NHCO (4- to 6-memberedheterocycloalkyl), and NHCOC₂-C₆ alkynyl;

-   -   wherein R⁷ is independently selected from C₁-C₆ alkyl, C₁-C₆        haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halo, CN, COC₁-C₆        alkyl, CO₂C₁-C₆ alkyl, CO₂C₃-C₆ cycloalkyl, OCOC₁-C₆ alkyl,        OCOC₆-C₁₀ aryl, OCO (5- to 10-membered heteroaryl), OCO (3- to        7-membered heterocycloalkyl), C₆-C₁₀ aryl, 5- to 10-membered        heteroaryl, CONR⁸R⁹, SF₅, S(O₂)C₁-C₆ alkyl, C₃-C₇ cycloalkyl and        4- to 6-membered heterocycloalkyl, wherein the C₁-C₆ alkyl is        optionally substituted with one to two C₁-C₆ alkoxy.    -   In some embodiments, the substituted ring B is

-   -    wherein each R⁶ is independently selected from C₁-C₆ alkyl,        C₃-C₇ cycloalkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆        haloalkoxy, halo, CN, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl,        CO—C₁-C₆ alkyl; CONR⁸R⁹, and 4- to 6-membered heterocycloalkyl,        wherein the C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₇ cycloalkyl and        4- to 6-membered heterocycloalkyl is optionally substituted with        one or more substituents each independently selected from        hydroxy, halo, CN, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰,        COOC₁-C₆ alkyl, CONR⁸R⁹, 4- to 6-membered heterocycloalkyl,        C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆ alkyl,        OCOC₆-C₁₀ aryl, OCO (5- to 10-membered heteroaryl), OCO (4- to        6-membered heterocycloalkyl), NHCOC₁-C₆ alkyl, NHCOC₆-C₁₀ aryl,        NHCO (5- to 10-membered heteroaryl), NHCO (4- to 6-membered        heterocycloalkyl), and NHCOC₂-C₆ alkynyl;    -   wherein each R⁷ is independently selected from C₁-C₆ alkyl,        C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halo, CN,        COC₁-C₆ alkyl, CO₂C₁-C₆ alkyl, CO₂C₃-C₆ cycloalkyl, OCOC₁-C₆        alkyl, OCOC₆-C₁₀ aryl, OCO (5- to 10-membered heteroaryl), OCO        (3- to 7-membered heterocycloalkyl), C₆-C₁₀ aryl, 5- to        10-membered heteroaryl, CONR⁸R⁹, SF₅, S(O₂)C₁-C₆ alkyl, C₃-C₇        cycloalkyl and 4- to 6-membered heterocycloalkyl, wherein the        C₁-C₆ alkyl is optionally substituted with one to two C₁-C₆        alkoxy;        or at least one pair of R⁶ and R⁷ on adjacent atoms, taken        together with the atoms connecting them, independently form at        least one C₄-C₇ carbocyclic ring or at least one 5-to-7-membered        heterocyclic ring containing 1 or 2 heteroatoms independently        selected from O, N, and S, wherein the carbocyclic ring or        heterocyclic ring is optionally independently substituted with        one or more substituents independently selected from hydroxy,        halo, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆        alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹.    -   In some embodiments, the substituted ring B is

-   -    wherein each R⁶ is independently selected from C₁-C₆ alkyl,        C₃-C₇ cycloalkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆        haloalkoxy, halo, CN, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl,        CO—C₁-C₆ alkyl; CONR⁸R⁹, and 4- to 6-membered heterocycloalkyl,        wherein the C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₇ cycloalkyl and        4- to 6-membered heterocycloalkyl is optionally substituted with        one or more substituents each independently selected from        hydroxy, halo, CN, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰,        COOC₁-C₆ alkyl, CONR⁸R⁹, 4- to 6-membered heterocycloalkyl,        C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆ alkyl,        OCOC₆-C₁₀ aryl, OCO (5- to 10-membered heteroaryl), OCO (4- to        6-membered heterocycloalkyl), NHCOC₁-C₆ alkyl, NHCOC₆-C₁₀ aryl,        NHCO (5- to 10-membered heteroaryl), NHCO (4- to 6-membered        heterocycloalkyl), and NHCOC₂-C₆ alkynyl;    -   wherein each R⁷ is independently selected from C₁-C₆ alkyl,        C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halo, CN,        COC₁-C₆ alkyl, CO₂C₁-C₆ alkyl, CO₂C₃-C₆ cycloalkyl, OCOC₁-C₆        alkyl, OCOC₆-C₁₀ aryl, OCO (5- to 10-membered heteroaryl), OCO        (3- to 7-membered heterocycloalkyl), C₆-C₁₀ aryl, 5- to        10-membered heteroaryl, CONR⁸R⁹, SF₅, S(O₂)C₁-C₆ alkyl, C₃-C₇        cycloalkyl and 4- to 6-membered heterocycloalkyl, wherein the        C₁-C₆ alkyl is optionally substituted with one to two C₁-C₆        alkoxy;        or at least one pair of R⁶ and R⁷ on adjacent atoms, taken        together with the atoms connecting them, independently form at        least one C₄-C₇ carbocyclic ring or at least one 5-to-7-membered        heterocyclic ring containing 1 or 2 heteroatoms independently        selected from O, N, and S, wherein the carbocyclic ring or        heterocyclic ring is optionally independently substituted with        one or more substituents independently selected from hydroxy,        halo, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆        alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹.    -   In some embodiments, the substituted ring B is

-   -    wherein each R⁶ is independently selected from C₁-C₆ alkyl,        C₃-C₇ cycloalkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆        haloalkoxy, halo, CN, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl,        CO—C₁-C₆ alkyl; CONR⁸R⁹, and 4- to 6-membered heterocycloalkyl,        wherein the C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₇ cycloalkyl and        4- to 6-membered heterocycloalkyl is optionally substituted with        one or more substituents each independently selected from        hydroxy, halo, CN, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰,        COOC₁-C₆ alkyl, CONR⁸R⁹, 4- to 6-membered heterocycloalkyl,        C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆ alkyl,        OCOC₆-C₁₀ aryl, OCO (5- to 10-membered heteroaryl), OCO (4- to        6-membered heterocycloalkyl), NHCOC₁-C₆ alkyl, NHCOC₆-C₁₀ aryl,        NHCO (5- to 10-membered heteroaryl), NHCO (4- to 6-membered        heterocycloalkyl), and NHCOC₂-C₆ alkynyl;    -   wherein each R⁷ is independently selected from C₁-C₆ alkyl,        C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halo, CN,        COC₁-C₆ alkyl, CO₂C₁-C₆ alkyl, CO₂C₃-C₆ cycloalkyl, OCOC₁-C₆        alkyl, OCOC₆-C₁₀ aryl, OCO (5- to 10-membered heteroaryl), OCO        (3- to 7-membered heterocycloalkyl), C₆-C₁₀ aryl, 5- to        10-membered heteroaryl, CONR⁸R⁹, SF₅, S(O₂)C₁-C₆ alkyl, C₃-C₇        cycloalkyl and 4- to 6-membered heterocycloalkyl, wherein the        C₁-C₆ alkyl is optionally substituted with one to two C₁-C₆        alkoxy;        or at least one pair of R⁶ and R⁷ on adjacent atoms, taken        together with the atoms connecting them, independently form at        least one C₄-C₇ carbocyclic ring or at least one 5-to-7-membered        heterocyclic ring containing 1 or 2 heteroatoms independently        selected from O, N, and S, wherein the carbocyclic ring or        heterocyclic ring is optionally independently substituted with        one or more substituents independently selected from hydroxy,        halo, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆        alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹.    -   In some embodiments, the substituted ring B is

-   -    wherein each R⁶ is independently selected from C₁-C₆ alkyl,        C₃-C₇ cycloalkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆        haloalkoxy, halo, CN, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl,        CO—C₁-C₆ alkyl; CONR⁸R⁹, and 4- to 6-membered heterocycloalkyl,        wherein the C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₇ cycloalkyl and        4- to 6-membered heterocycloalkyl is optionally substituted with        one or more substituents each independently selected from        hydroxy, halo, CN, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰,        COOC₁-C₆ alkyl, CONR⁸R⁹, 4- to 6-membered heterocycloalkyl,        C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆ alkyl,        OCOC₆-C₁₀ aryl, OCO (5- to 10-membered heteroaryl), OCO (4- to        6-membered heterocycloalkyl), NHCOC₁-C₆ alkyl, NHCOC₆-C₁₀ aryl,        NHCO (5- to 10-membered heteroaryl), NHCO (4- to 6-membered        heterocycloalkyl), and NHCOC₂-C₆ alkynyl;    -   wherein each R⁷ is independently selected from C₁-C₆ alkyl,        C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halo, CN,        COC₁-C₆ alkyl, CO₂C₁-C₆ alkyl, CO₂C₃-C₆ cycloalkyl, OCOC₁-C₆        alkyl, OCOC₆-C₁₀ aryl, OCO (5- to 10-membered heteroaryl), OCO        (3- to 7-membered heterocycloalkyl), C₆-C₁₀ aryl, 5- to        10-membered heteroaryl, CONR⁸R⁹, SF₅, S(O₂)C₁-C₆ alkyl, C₃-C₇        cycloalkyl and 4- to 6-membered heterocycloalkyl, wherein the        C₁-C₆ alkyl is optionally substituted with one to two C₁-C₆        alkoxy;    -   or R⁶ and R⁷, taken together with the atoms connecting them,        independently form a C₄-C₇ carbocyclic ring or at least one        5-to-7-membered heterocyclic ring containing 1 or 2 heteroatoms        independently selected from O, N, and S, wherein the carbocyclic        ring or heterocyclic ring is optionally independently        substituted with one or more substituents independently selected        from hydroxy, halo, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰        COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹.    -   In some embodiments, the substituted ring B is

-   -    wherein each R⁶ is independently selected from C₁-C₆ alkyl,        C₃-C₇ cycloalkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆        haloalkoxy, halo, CN, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl,        CO—C₁-C₆ alkyl; CONR⁸R⁹, and 4- to 6-membered heterocycloalkyl,        wherein the C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₇ cycloalkyl and        4- to 6-membered heterocycloalkyl is optionally substituted with        one or more substituents each independently selected from        hydroxy, halo, CN, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰,        COOC₁-C₆ alkyl, CONR⁸R⁹, 4- to 6-membered heterocycloalkyl,        C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆ alkyl,        OCOC₆-C₁₀ aryl, OCO (5- to 10-membered heteroaryl), OCO (4- to        6-membered heterocycloalkyl), NHCOC₁-C₆ alkyl, NHCOC₆-C₁₀ aryl,        NHCO (5- to 10-membered heteroaryl), NHCO (4- to 6-membered        heterocycloalkyl), and NHCOC₂-C₆ alkynyl;    -   wherein each R⁷ is independently selected from C₁-C₆ alkyl,        C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halo, CN,        COC₁-C₆ alkyl, CO₂C₁-C₆ alkyl, CO₂C₃-C₆ cycloalkyl, OCOC₁-C₆        alkyl, OCOC₆-C₁₀ aryl, OCO (5- to 10-membered heteroaryl), OCO        (3- to 7-membered heterocycloalkyl), C₆-C₁₀ aryl, 5- to        10-membered heteroaryl, CONR⁸R⁹, SF₅, S(O₂)C₁-C₆ alkyl, C₃-C₇        cycloalkyl and 4- to 6-membered heterocycloalkyl, wherein the        C₁-C₆ alkyl is optionally substituted with one to two C₁-C₆        alkoxy;    -   or at least one pair of R⁶ and R⁷ on adjacent atoms, taken        together with the atoms connecting them, independently form at        least one C₄-C₇ carbocyclic ring or at least one 5-to-7-membered        heterocyclic ring containing 1 or 2 heteroatoms independently        selected from O, N, and S, wherein the carbocyclic ring or        heterocyclic ring is optionally independently substituted with        one or more substituents independently selected from hydroxy,        hydroxymethyl, halo, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹,        CH₂NR⁸R⁹, ═NR¹⁰ COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹;

The Group R³

In some embodiments, R³ is selected from hydrogen, C₁-C₆ alkyl, and

wherein the C₁-C₂ alkylene group is optionally substituted with oxo.

In some embodiments, R³ is hydrogen.

In some embodiments, R³ is cyano.

In some embodiments, R³ is hydroxy.

In some embodiments, R³ is C₁-C₆ alkoxy. In some embodiments, R³ isC₁-C₆ alkyl.

In some embodiments, R³ is methyl.

In some embodiments, R³ is

wherein the C₁-C₂ alkylene group is optionally substituted with oxo.

In some embodiments, R³ is —CH₂R¹⁴.

In some embodiments, R³ is —C(O)R¹⁴.

In some embodiments, R³ is —CH₂CH₂R¹⁴.

In some embodiments, R³ is —CHR¹⁴CH₃.

In some embodiments, R³ is —CH₂C(O)R¹⁴.

In some embodiments, R³ is —C(O)CH₂R¹⁴.

In some embodiments, R³ is CO₂C₁-C₆ alkyl.

The Group R¹⁴

In some embodiments, R¹⁴ is hydrogen, C₁-C₆ alkyl, 5- to 10-memberedmonocyclic or bicyclic heteroaryl or C₆-C₁₀ monocyclic or bicyclic aryl,wherein each C₁-C₆ alkyl, aryl or heteroaryl is optionally independentlysubstituted with 1 or 2 R⁶.

In some embodiments, R¹⁴ is hydrogen or C₁-C₆ alkyl.

In some embodiments, R¹⁴ is hydrogen, 5- to 10-membered monocyclic orbicyclic heteroaryl or C₆-C₁₀ monocyclic or bicyclic aryl, wherein eachC₁-C₆ alkyl, aryl or heteroaryl is optionally independently substitutedwith 1 or 2 R⁶.

In some embodiments, R is hydrogen.

In some embodiments, R¹⁴ is C₁-C₆ alkyl.

In some embodiments, R¹⁴ is methyl.

In some embodiments, R¹⁴ is 5- to 10-membered monocyclic or bicyclicheteroaryl optionally independently substituted with 1 or 2 R⁶.

In some embodiments, R¹⁴ is C₆-C₁₀ monocyclic or bicyclic aryloptionally independently substituted with 1 or 2 R⁶.

The Moiety S(═O)(NHR³)═N—

In some embodiments, the sulfur in the moiety S(═O)(NHR³)═N— has (S)stereochemistry.

In some embodiments, the sulfur in the moiety S(═O)(NHR³)═N— has (R)stereochemistry.

The Group R¹⁰

In some embodiments, R¹⁰ is C₁-C₆ alkyl.

In some embodiments, R¹⁰ is methyl.

In some embodiments, R¹⁰ is ethyl.

The groups R⁸ and R⁹

In some embodiments, each of R⁸ and R⁹ at each occurrence isindependently selected from hydrogen, C₁-C₆ alkyl, (C═NR¹³)NR¹¹R¹²,S(O₂)C₁-C₆ alkyl, S(O₂)NR¹¹R¹², COR¹³, CO₂R¹³ and CONR¹¹R¹², wherein theC₁-C₆ alkyl is optionally substituted with one or more hydroxy, halo,C₁-C₆ alkoxy, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₇cycloalkyl or 3- to 7-membered heterocycloalkyl; or R⁸ and R⁹ takentogether with the nitrogen they are attached to form a 3- to 7-memberedring optionally containing one or more heteroatoms in addition to thenitrogen they are attached to.

In some embodiments, each of R⁸ and R⁹ at each occurrence isindependently selected from hydrogen, C₁-C₆ alkyl, (C═NR¹³)NR¹¹R¹²,S(O₂)C₁-C₆ alkyl, S(O₂)NR¹¹R¹², COR¹³, CO₂R¹³ and CONR¹¹R¹², wherein theC₁-C₆ alkyl is optionally substituted with one or more hydroxy, halo,C₁-C₆ alkoxy, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₇cycloalkyl or 3- to 7-membered heterocycloalkyl; or R⁸ and R⁹ takentogether with the nitrogen they are attached to form a 3- to 7-memberedring optionally containing one or more heteroatoms in addition to thenitrogen they are attached to.

In some embodiments, each of R⁸ and R⁹ at each occurrence is hydrogen,

In some embodiments, each R⁸ at each occurrence is hydrogen and each R⁹at each occurrence is C₁-C₆ alkyl.

In some embodiments, each R⁸ at each occurrence is hydrogen and each R⁹at each occurrence is methyl.

In some embodiments, each R⁸ at each occurrence is hydrogen and each R⁹at each occurrence is ethyl.

In some embodiments, each of R⁸ and R⁹ at each occurrence is methyl.

In some embodiments, each of R⁸ and R⁹ at each occurrence is ethyl.

In some embodiments, R⁸ and R⁹ taken together with the nitrogen they areattached to form a 3-membered ring.

In some embodiments, R⁸ and R⁹ taken together with the nitrogen they areattached to form a 4-membered ring.

In some embodiments, R⁸ and R⁹ taken together with the nitrogen they areattached to form a 5-membered ring.

In some embodiments, R⁸ and R⁹ taken together with the nitrogen they areattached to form a 6-membered ring optionally containing one or moreoxygen atoms in addition to the nitrogen they are attached to.

In some embodiments, R⁸ and R⁹ taken together with the nitrogen they areattached to form a 6-membered ring optionally containing one or morenitrogen atoms in addition to the nitrogen they are attached to.

In some embodiments, R⁸ and R⁹ taken together with the nitrogen they areattached to form a 7-membered ring.

The Group R¹³

In some embodiments, R¹³ is C₁-C₆ alkyl.

In some embodiments, R¹³ is methyl.

In some embodiments, R¹³ is ethyl.

In some embodiments, R¹³ is C₆-C₁₀ aryl.

In some embodiments, R¹³ is phenyl.

In some embodiments, R¹³ is 5- to 10-membered heteroaryl.

The groups R¹⁴ and R¹²

In some embodiments, each of R¹⁴ and R¹² at each occurrence isindependently selected from hydrogen and C₁-C₆ alkyl.

In some embodiments, each of R¹⁴ and R¹² at each occurrence is hydrogen,

In some embodiments, each R¹⁴ at each occurrence is hydrogen and eachR¹² at each occurrence is C₁-C₆ alkyl.

In some embodiments, each R¹⁴ at each occurrence is hydrogen and eachR¹² at each occurrence is methyl.

In some embodiments, each R¹⁴ at each occurrence is hydrogen and eachR¹² at each occurrence is ethyl.

In some embodiments, each of R¹⁴ and R¹² at each occurrence is methyl.

In some embodiments, each of R¹⁴ and R¹² at each occurrence is ethyl.

In some embodiments of the compound of formula AA,

the substituted ring A is

and R¹ is selected from:C₁-C₆ alkyl optionally substituted with one or more hydroxy; C₃-C₇cycloalkyl optionally substituted with one or more hydroxy; 3- to7-membered heterocycloalkyl optionally substituted with one or morehydroxy; C₁-C₆ alkyl substituted with one or more oxo; C₃-C₇ cycloalkylsubstituted with one or more oxo; C₁-C₆ alkyl substituted with one ormore C₁-C₆ alkoxy; C₃-C₇ cycloalkyl substituted with one or more C₁-C₆alkoxy; C₁-C₆ haloalkyl; C₁-C₆ alkoxy; C₁-C₆ haloalkoxy; halo; CN; NO₂;COC₁-C₆ alkyl; CO—C₆-C₁₀ aryl; CO (5- to 10-membered heteroaryl);CO₂C₁-C₆ alkyl; CO₂C₃-C₈ cycloalkyl; OCOC₁-C₆ alkyl; OCOC₆-C₁₀ aryl; OCO(5- to 10-membered heteroaryl); OCO (3- to 7-membered heterocycloalkyl);C₆-C₁₀ aryl; 5- to 10-membered heteroaryl; NH₂; NHC₁-C₆ alkyl; N(C₁-C₆alkyl)₂; CONR⁸R⁹; SF₅; and S(O₂)C₁-C₆ alkyl.

In some embodiments of the compound of formula AA,

the substituted ring A is

and R¹ is selected from:

-   -   1-hydroxy-2-methylpropan-2-yl; methyl; isopropyl;        2-hydroxy-2-propyl; hydroxymethyl; 1-hydroxyethyl;        2-hydroxyethyl; 1-hydroxy-2-propyl; 1-hydroxy-1-cyclopropyl;        1-hydroxy-1-cyclobutyl; 1-hydroxy-1-cyclopentyl;        1-hydroxy-1-cyclohexyl; morpholinyl; 1,3-dioxolan-2-yl; COCH₃;        COCH₂CH₃; 2-methoxy-2-propyl; (dimethylamino)methyl;        1-(dimethylamino)ethyl; fluoro; chloro; phenyl; pyridyl;        pyrazolyl; and S(O₂)CH₃.

In some embodiments of the compound of formula AA,

the substituted ring A is

and R¹ is selected from:

-   -   C₁-C₆ alkyl optionally substituted with one or more hydroxy;        C₃-C₇ cycloalkyl optionally substituted with one or more        hydroxy; 3- to 7-membered heterocycloalkyl optionally        substituted with one or more hydroxy; C₁-C₆ alkyl substituted        with one or more oxo; C₃-C₇ cycloalkyl substituted with one or        more oxo; C₁-C₆ alkyl substituted with one or more C₁-C₆ alkoxy;        C₃-C₇ cycloalkyl substituted with one or more C₁-C₆ alkoxy;        C₁-C₆ alkyl substituted with one or more NR⁸R⁹; 3- to 7-membered        heterocycloalkyl substituted with one or more NR⁸R⁹; C₁-C₆        haloalkyl; C₁-C₆ alkoxy; C₁-C₆ haloalkoxy; halo; CN; NO₂;        COC₁-C₆ alkyl; CO—C₆-C₁₀ aryl; CO (5- to 10-membered        heteroaryl); CO₂C₁-C₆ alkyl; CO₂C₃-C₈ cycloalkyl; OCOC₁-C₆        alkyl; OCOC₆-C₁₀ aryl; OCO (5- to 10-membered heteroaryl); OCO        (3- to 7-membered heterocycloalkyl); C₆-C₁₀ aryl; 5- to        10-membered heteroaryl; NH₂; NHC₁-C₆ alkyl; N(C₁-C₆ alkyl)₂;        CONR⁸R⁹; SF₅; and S(O₂)C₁-C₆ alkyl.

In some embodiments of the compound of formula AA,

the substituted ring A is

and R¹ is selected from:

-   -   1-hydroxy-2-methylpropan-2-yl; methyl; isopropyl;        2-hydroxy-2-propyl; hydroxymethyl; 1-hydroxyethyl;        2-hydroxyethyl; 1-hydroxy-2-propyl; 1-hydroxy-1-cyclopropyl;        1-hydroxy-1-cyclobutyl; 1-hydroxy-1-cyclopentyl;        1-hydroxy-1-cyclohexyl; morpholinyl; 1,3-dioxolan-2-yl; COCH₃;        COCH₂CH₃; 2-methoxy-2-propyl; (dimethylamino)methyl;        1-(dimethylamino)ethyl; fluoro; chloro; phenyl; pyridyl;        pyrazolyl; and S(O₂)CH₃.

In some embodiments of the compound of formula AA,

the substituted ring A is

and R¹ is selected from:

-   -   C₁-C₆ alkyl optionally substituted with one or more hydroxy;        C₃-C₇ cycloalkyl optionally substituted with one or more        hydroxy; 3- to 7-membered heterocycloalkyl optionally        substituted with one or more hydroxy; C₁-C₆ alkyl substituted        with one or more oxo; C₃-C₇ cycloalkyl substituted with one or        more oxo; C₁-C₆ alkyl substituted with one or more C₁-C₆ alkoxy;        C₃-C₇ cycloalkyl substituted with one or more C₁-C₆ alkoxy;        C₁-C₆ alkyl substituted with one or more NR⁸R⁹; 3- to 7-membered        heterocycloalkyl substituted with one or more NR⁸R⁹; C₁-C₆        haloalkyl; C₁-C₆ alkoxy; C₁-C₆ haloalkoxy; halo; CN; NO₂;        COC₁-C₆ alkyl; CO—C₆-C₁₀ aryl; CO (5- to 10-membered        heteroaryl); CO₂C₁-C₆ alkyl; CO₂C₃-C₈ cycloalkyl; OCOC₁-C₆        alkyl; OCOC₆-C₁₀ aryl; OCO (5- to 10-membered heteroaryl); OCO        (3- to 7-membered heterocycloalkyl); C₆-C₁₀ aryl; 5- to        10-membered heteroaryl; NH₂; NHC₁-C₆ alkyl; N(C₁-C₆ alkyl)₂;        CONR⁸R⁹; SF₅; and S(O₂)C₁-C₆ alkyl.

In some embodiments of the compound of formula AA,

the substituted ring A is

and R¹ is selected from:

-   -   1-hydroxy-2-methylpropan-2-yl; methyl; isopropyl;        2-hydroxy-2-propyl; hydroxymethyl; 1-hydroxyethyl;        2-hydroxyethyl; 1-hydroxy-2-propyl; 1-hydroxy-1-cyclopropyl;        1-hydroxy-1-cyclobutyl; 1-hydroxy-1-cyclopentyl;        1-hydroxy-1-cyclohexyl; morpholinyl; 1,3-dioxolan-2-yl; COCH₃;        COCH₂CH₃; 2-methoxy-2-propyl; (dimethylamino)methyl;        1-(dimethylamino)ethyl; fluoro; chloro; phenyl; pyridyl;        pyrazolyl; and S(O₂)CH₃.

In some embodiments of the compound of formula AA,

the substituted ring A is

and R¹ is selected from:

-   -   C₁-C₆ alkyl optionally substituted with one or more hydroxy;        C₃-C₇ cycloalkyl optionally substituted with one or more        hydroxy; 3- to 7-membered heterocycloalkyl optionally        substituted with one or more hydroxy; C₁-C₆ alkyl substituted        with one or more oxo; C₃-C₇ cycloalkyl substituted with one or        more oxo; C₁-C₆ alkyl substituted with one or more C₁-C₆ alkoxy;        C₃-C₇ cycloalkyl substituted with one or more C₁-C₆ alkoxy;        C₁-C₆ alkyl substituted with one or more NR⁸R⁹; 3- to 7-membered        heterocycloalkyl substituted with one or more NR⁸R⁹; C₁-C₆        haloalkyl; C₁-C₆ alkoxy; C₁-C₆ haloalkoxy; halo; CN; NO₂;        COC₁-C₆ alkyl; CO—C₆-C₁₀ aryl; CO (5- to 10-membered        heteroaryl); CO₂C₁-C₆ alkyl; CO₂C₃-C₈ cycloalkyl; OCOC₁-C₆        alkyl; OCOC₆-C₁₀ aryl; OCO (5- to 10-membered heteroaryl); OCO        (3- to 7-membered heterocycloalkyl); C₆-C₁₀ aryl; 5- to        10-membered heteroaryl; NH₂; NHC₁-C₆ alkyl; N(C₁-C₆ alkyl)₂;        CONR⁸R⁹; SF₅; and S(O₂)C₁-C₆ alkyl.

In some embodiments of the compound of formula AA,

the substituted ring A is

and R¹ is selected from:

-   -   1-hydroxy-2-methylpropan-2-yl; methyl; isopropyl;        2-hydroxy-2-propyl; hydroxymethyl; 1-hydroxyethyl;        2-hydroxyethyl; 1-hydroxy-2-propyl; 1-hydroxy-1-cyclopropyl;        1-hydroxy-1-cyclobutyl; 1-hydroxy-1-cyclopentyl;        1-hydroxy-1-cyclohexyl; morpholinyl; 1,3-dioxolan-2-yl; COCH₃;        COCH₂CH₃; 2-methoxy-2-propyl; (dimethylamino)methyl;        1-(dimethylamino)ethyl; fluoro; chloro; phenyl; pyridyl;        pyrazolyl; and S(O₂)CH₃.

In some embodiments of the compound of formula AA,

the substituted ring A is

and R¹ is selected from:

-   -   C₁-C₆ alkyl optionally substituted with one or more hydroxy;        C₃-C₇ cycloalkyl optionally substituted with one or more        hydroxy; 3- to 7-membered heterocycloalkyl optionally        substituted with one or more hydroxy; C₁-C₆ alkyl substituted        with one or more oxo; C₃-C₇ cycloalkyl substituted with one or        more oxo; C₁-C₆ alkyl substituted with one or more C₁-C₆ alkoxy;        C₃-C₇ cycloalkyl substituted with one or more C₁-C₆ alkoxy;        C₁-C₆ alkyl substituted with one or more NR⁸R⁹; 3- to 7-membered        heterocycloalkyl substituted with one or more NR⁸R⁹; C₁-C₆        haloalkyl; C₁-C₆ alkoxy; C₁-C₆ haloalkoxy; halo; CN; NO₂;        COC₁-C₆ alkyl; CO—C₆-C₁₀ aryl; CO (5- to 10-membered        heteroaryl); CO₂C₁-C₆ alkyl; CO₂C₃-C₈ cycloalkyl; OCOC₁-C₆        alkyl; OCOC₆-C₁₀ aryl; OCO (5- to 10-membered heteroaryl); OCO        (3- to 7-membered heterocycloalkyl); C₆-C₁₀ aryl; 5- to        10-membered heteroaryl; NH₂; NHC₁-C₆ alkyl; N(C₁-C₆ alkyl)₂;        CONR⁸R⁹; SF₅; and S(O₂)C₁-C₆ alkyl.

In some embodiments of the compound of formula AA,

the substituted ring A is

and R¹ is selected from:

-   -   1-hydroxy-2-methylpropan-2-yl; methyl; isopropyl;        2-hydroxy-2-propyl; hydroxymethyl; 1-hydroxyethyl;        2-hydroxyethyl; 1-hydroxy-2-propyl; 1-hydroxy-1-cyclopropyl;        1-hydroxy-1-cyclobutyl; 1-hydroxy-1-cyclopentyl;        1-hydroxy-1-cyclohexyl; morpholinyl; 1,3-dioxolan-2-yl; COCH₃;        COCH₂CH₃; 2-methoxy-2-propyl; (dimethylamino)methyl;        1-(dimethylamino)ethyl; fluoro; chloro; phenyl; pyridyl;        pyrazolyl; and S(O₂)CH₃.

In some embodiments of the compound of formula AA,

the substituted ring A is

and R¹ is selected from:

-   -   C₁-C₆ alkyl optionally substituted with one or more hydroxy;        C₃-C₇ cycloalkyl optionally substituted with one or more        hydroxy; 3- to 7-membered heterocycloalkyl optionally        substituted with one or more hydroxy; C₁-C₆ alkyl substituted        with one or more oxo; C₃-C₇ cycloalkyl substituted with one or        more oxo; C₁-C₆ alkyl substituted with one or more C₁-C₆ alkoxy;        C₃-C₇ cycloalkyl substituted with one or more C₁-C₆ alkoxy;        C₁-C₆ alkyl substituted with one or more NR⁸R⁹; 3- to 7-membered        heterocycloalkyl substituted with one or more NR⁸R⁹; C₁-C₆        haloalkyl; C₁-C₆ alkoxy; C₁-C₆ haloalkoxy; halo; CN; NO₂;        COC₁-C₆ alkyl; CO—C₆-C₁₀ aryl; CO (5- to 10-membered        heteroaryl); CO₂C₁-C₆ alkyl; CO₂C₃-C₈ cycloalkyl; OCOC₁-C₆        alkyl; OCOC₆-C₁₀ aryl; OCO (5- to 10-membered heteroaryl); OCO        (3- to 7-membered heterocycloalkyl); C₆-C₁₀ aryl; 5- to        10-membered heteroaryl; NH₂; NHC₁-C₆ alkyl; N(C₁-C₆ alkyl)₂;        CONR⁸R⁹; SF₅; and S(O₂)C₁-C₆ alkyl.

In some embodiments of the compound of formula AA,

the substituted ring A is

and R¹ is selected from:

-   -   1-hydroxy-2-methylpropan-2-yl; methyl; isopropyl;        2-hydroxy-2-propyl; hydroxymethyl; 1-hydroxyethyl;        2-hydroxyethyl; 1-hydroxy-2-propyl; 1-hydroxy-1-cyclopropyl;        1-hydroxy-1-cyclobutyl; 1-hydroxy-1-cyclopentyl;        1-hydroxy-1-cyclohexyl; morpholinyl; 1,3-dioxolan-2-yl; COCH₃;        COCH₂CH₃; 2-methoxy-2-propyl; (dimethylamino)methyl;        1-(dimethylamino)ethyl; fluoro; chloro; phenyl; pyridyl;        pyrazolyl; and S(O₂)CH₃.

In some embodiments of the compound of formula AA,

the substituted ring A is

and R¹ is selected from:

-   -   C₁-C₆ alkyl optionally substituted with one or more hydroxy;        C₃-C₇ cycloalkyl optionally substituted with one or more        hydroxy; 3- to 7-membered heterocycloalkyl optionally        substituted with one or more hydroxy; C₁-C₆ alkyl substituted        with one or more oxo; C₃-C₇ cycloalkyl substituted with one or        more oxo; C₁-C₆ alkyl substituted with one or more C₁-C₆ alkoxy;        C₃-C₇ cycloalkyl substituted with one or more C₁-C₆ alkoxy;        C₁-C₆ alkyl substituted with one or more NR⁸R⁹; 3- to 7-membered        heterocycloalkyl substituted with one or more NR⁸R⁹; C₁-C₆        haloalkyl; C₁-C₆ alkoxy; C₁-C₆ haloalkoxy; halo; CN; NO₂;        COC₁-C₆ alkyl; CO—C₆-C₁₀ aryl; CO (5- to 10-membered        heteroaryl); CO₂C₁-C₆ alkyl; CO₂C₃-C₈ cycloalkyl; OCOC₁-C₆        alkyl; OCOC₆-C₁₀ aryl; OCO (5- to 10-membered heteroaryl); OCO        (3- to 7-membered heterocycloalkyl); C₆-C₁₀ aryl; 5- to        10-membered heteroaryl; NH₂; NHC₁-C₆ alkyl; N(C₁-C₆ alkyl)₂;        CONR⁸R⁹; SF₅; and S(O₂)C₁-C₆ alkyl.

In some embodiments of the compound of formula AA,

the substituted ring A is

and R¹ is selected from:

-   -   1-hydroxy-2-methylpropan-2-yl; methyl; isopropyl;        2-hydroxy-2-propyl; hydroxymethyl; 1-hydroxyethyl;        2-hydroxyethyl; 1-hydroxy-2-propyl; 1-hydroxy-1-cyclopropyl;        1-hydroxy-1-cyclobutyl; 1-hydroxy-1-cyclopentyl;        1-hydroxy-1-cyclohexyl; morpholinyl; 1,3-dioxolan-2-yl; COCH₃;        COCH₂CH₃; 2-methoxy-2-propyl; (dimethylamino)methyl;        1-(dimethylamino)ethyl; fluoro; chloro; phenyl; pyridyl;        pyrazolyl; and S(O₂)CH₃.

In some embodiments of the compound of formula AA,

the substituted ring A is

and R¹ is selected from:

-   -   C₁-C₆ alkyl optionally substituted with one or more hydroxy;        C₃-C₇ cycloalkyl optionally substituted with one or more        hydroxy; 3- to 7-membered heterocycloalkyl optionally        substituted with one or more hydroxy; C₁-C₆ alkyl substituted        with one or more oxo; C₃-C₇ cycloalkyl substituted with one or        more oxo; C₁-C₆ alkyl substituted with one or more C₁-C₆ alkoxy;        C₃-C₇ cycloalkyl substituted with one or more C₁-C₆ alkoxy;        C₁-C₆ alkyl substituted with one or more NR⁸R⁹; 3- to 7-membered        heterocycloalkyl substituted with one or more NR⁸R⁹; C₁-C₆        haloalkyl; C₁-C₆ alkoxy; C₁-C₆ haloalkoxy; halo; CN; NO₂;        COC₁-C₆ alkyl; CO—C₆-C₁₀ aryl; CO (5- to 10-membered        heteroaryl); CO₂C₁-C₆ alkyl; CO₂C₃-C₈ cycloalkyl; OCOC₁-C₆        alkyl; OCOC₆-C₁₀ aryl; OCO (5- to 10-membered heteroaryl); OCO        (3- to 7-membered heterocycloalkyl); C₆-C₁₀ aryl; 5- to        10-membered heteroaryl; NH₂; NHC₁-C₆ alkyl; N(C₁-C₆ alkyl)₂;        CONR⁸R⁹; SF₅; and S(O₂)C₁-C₆ alkyl.

In some embodiments of the compound of formula AA,

the substituted ring A is

and R¹ is selected from:

-   -   1-hydroxy-2-methylpropan-2-yl; methyl; isopropyl;        2-hydroxy-2-propyl; hydroxymethyl; 1-hydroxyethyl;        2-hydroxyethyl; 1-hydroxy-2-propyl; 1-hydroxy-1-cyclopropyl;        1-hydroxy-1-cyclobutyl; 1-hydroxy-1-cyclopentyl;        1-hydroxy-1-cyclohexyl; morpholinyl; 1,3-dioxolan-2-yl; COCH₃;        COCH₂CH₃; 2-methoxy-2-propyl; (dimethylamino)methyl;        1-(dimethylamino)ethyl; fluoro; chloro; phenyl; pyridyl;        pyrazolyl; and S(O₂)CH₃.

In some embodiments of the compound of formula AA,

the substituted ring A is

and R¹ is selected from:

-   -   C₁-C₆ alkyl optionally substituted with one or more hydroxy;        C₃-C₇ cycloalkyl optionally substituted with one or more        hydroxy; 3- to 7-membered heterocycloalkyl optionally        substituted with one or more hydroxy; C₁-C₆ alkyl substituted        with one or more oxo; C₃-C₇ cycloalkyl substituted with one or        more oxo; C₁-C₆ alkyl substituted with one or more C₁-C₆ alkoxy;        C₃-C₇ cycloalkyl substituted with one or more C₁-C₆ alkoxy;        C₁-C₆ alkyl substituted with one or more NR⁸R⁹; 3- to 7-membered        heterocycloalkyl substituted with one or more NR⁸R⁹; C₁-C₆        haloalkyl; C₁-C₆ alkoxy; C₁-C₆ haloalkoxy; halo; CN; NO₂;        COC₁-C₆ alkyl; CO—C₆-C₁₀ aryl; CO (5- to 10-membered        heteroaryl); CO₂C₁-C₆ alkyl; CO₂C₃-C₈ cycloalkyl; OCOC₁-C₆        alkyl; OCOC₆-C₁₀ aryl; OCO (5- to 10-membered heteroaryl); OCO        (3- to 7-membered heterocycloalkyl); C₆-C₁₀ aryl; 5- to        10-membered heteroaryl; NH₂; NHC₁-C₆ alkyl; N(C₁-C₆ alkyl)₂;        CONR⁸R⁹; SF₅; and S(O₂)C₁-C₆ alkyl. In some embodiments of the        compound of formula AA,        the substituted ring A is

and R¹ is selected from:

-   -   1-hydroxy-2-methylpropan-2-yl; methyl; isopropyl;        2-hydroxy-2-propyl; hydroxymethyl; 1-hydroxyethyl;        2-hydroxyethyl; 1-hydroxy-2-propyl; 1-hydroxy-1-cyclopropyl;        1-hydroxy-1-cyclobutyl; 1-hydroxy-1-cyclopentyl;        1-hydroxy-1-cyclohexyl; morpholinyl; 1,3-dioxolan-2-yl; COCH₃;        COCH₂CH₃; 2-methoxy-2-propyl; (dimethylamino)methyl;        1-(dimethylamino)ethyl; fluoro; chloro; phenyl; pyridyl;        pyrazolyl; and S(O₂)CH₃.

In some embodiments of the compound of formula AA,

the substituted ring A is

and R¹ is selected from:

-   -   C₁-C₆ alkyl optionally substituted with one or more hydroxy;        C₃-C₇ cycloalkyl optionally substituted with one or more        hydroxy; 3- to 7-membered heterocycloalkyl optionally        substituted with one or more hydroxy; C₁-C₆ alkyl substituted        with one or more oxo; C₃-C₇ cycloalkyl substituted with one or        more oxo; C₁-C₆ alkyl substituted with one or more C₁-C₆ alkoxy;        C₃-C₇ cycloalkyl substituted with one or more C₁-C₆ alkoxy;        C₁-C₆ alkyl substituted with one or more NR⁸R⁹; 3- to 7-membered        heterocycloalkyl substituted with one or more NR⁸R⁹; C₁-C₆        haloalkyl; C₁-C₆ alkoxy; C₁-C₆ haloalkoxy; halo; CN; NO₂;        COC₁-C₆ alkyl; CO—C₆-C₁₀ aryl; CO (5- to 10-membered        heteroaryl); CO₂C₁-C₆ alkyl; CO₂C₃-C₈ cycloalkyl; OCOC₁-C₆        alkyl; OCOC₆-C₁₀ aryl; OCO (5- to 10-membered heteroaryl); OCO        (3- to 7-membered heterocycloalkyl); C₆-C₁₀ aryl; 5- to        10-membered heteroaryl; NH₂; NHC₁-C₆ alkyl; N(C₁-C₆ alkyl)₂;        CONR⁸R⁹; SF₅; and S(O₂)C₁-C₆ alkyl.

In some embodiments of the compound of formula AA,

the substituted ring A is

and R¹ is selected from:

-   -   1-hydroxy-2-methylpropan-2-yl; methyl; isopropyl;        2-hydroxy-2-propyl; hydroxymethyl; 1-hydroxyethyl;        2-hydroxyethyl; 1-hydroxy-2-propyl; 1-hydroxy-1-cyclopropyl;        1-hydroxy-1-cyclobutyl; 1-hydroxy-1-cyclopentyl;        1-hydroxy-1-cyclohexyl; morpholinyl; 1,3-dioxolan-2-yl; COCH₃;        COCH₂CH₃; 2-methoxy-2-propyl; (dimethylamino)methyl;        1-(dimethylamino)ethyl; fluoro; chloro; phenyl; pyridyl;        pyrazolyl; and S(O₂)CH₃.

In some embodiments of the compound of formula AA,

the substituted ring A is

and R¹ is selected from:

-   -   C₁-C₆ alkyl optionally substituted with one or more hydroxy;        C₃-C₇ cycloalkyl optionally substituted with one or more        hydroxy; 3- to 7-membered heterocycloalkyl optionally        substituted with one or more hydroxy; C₁-C₆ alkyl substituted        with one or more oxo; C₃-C₇ cycloalkyl substituted with one or        more oxo; C₁-C₆ alkyl substituted with one or more C₁-C₆ alkoxy;        C₃-C₇ cycloalkyl substituted with one or more C₁-C₆ alkoxy;        C₁-C₆ alkyl substituted with one or more NR⁸R⁹; 3- to 7-membered        heterocycloalkyl substituted with one or more NR⁸R⁹; C₁-C₆        haloalkyl; C₁-C₆ alkoxy; C₁-C₆ haloalkoxy; halo; CN; NO₂;        COC₁-C₆ alkyl; CO—C₆-C₁₀ aryl; CO (5- to 10-membered        heteroaryl); CO₂C₁-C₆ alkyl; CO₂C₃-C₈ cycloalkyl; OCOC₁-C₆        alkyl; OCOC₆-C₁₀ aryl; OCO (5- to 10-membered heteroaryl); OCO        (3- to 7-membered heterocycloalkyl); C₆-C₁₀ aryl; 5- to        10-membered heteroaryl; NH₂; NHC₁-C₆ alkyl; N(C₁-C₆ alkyl)₂;        CONR⁸R⁹; SF₅; and S(O₂)C₁-C₆ alkyl.

In some embodiments of the compound of formula AA,

the substituted ring A is

and R¹ is selected from:

-   -   1-hydroxy-2-methylpropan-2-yl; methyl; isopropyl;        2-hydroxy-2-propyl; hydroxymethyl; 1-hydroxyethyl;        2-hydroxyethyl; 1-hydroxy-2-propyl; 1-hydroxy-1-cyclopropyl;        1-hydroxy-1-cyclobutyl; 1-hydroxy-1-cyclopentyl;        1-hydroxy-1-cyclohexyl; morpholinyl; 1,3-dioxolan-2-yl; COCH₃;        COCH₂CH₃; 2-methoxy-2-propyl; (dimethylamino)methyl;        1-(dimethylamino)ethyl; fluoro; chloro; phenyl; pyridyl;        pyrazolyl; and S(O₂)CH₃.

In some embodiments of the compound of formula AA,

the substituted ring A is

and R¹ is selected from:

-   -   C₁-C₆ alkyl optionally substituted with one or more hydroxy;        C₃-C₇ cycloalkyl optionally substituted with one or more        hydroxy; 3- to 7-membered heterocycloalkyl optionally        substituted with one or more hydroxy; C₁-C₆ alkyl substituted        with one or more oxo; C₃-C₇ cycloalkyl substituted with one or        more oxo; C₁-C₆ alkyl substituted with one or more C₁-C₆ alkoxy;        C₃-C₇ cycloalkyl substituted with one or more C₁-C₆ alkoxy;        C₁-C₆ alkyl substituted with one or more NR⁸R⁹; 3- to 7-membered        heterocycloalkyl substituted with one or more NR⁸R⁹; C₁-C₆        haloalkyl; C₁-C₆ alkoxy; C₁-C₆ haloalkoxy; halo; CN; NO₂;        COC₁-C₆ alkyl; CO—C₆-C₁₀ aryl; CO (5- to 10-membered        heteroaryl); CO₂C₁-C₆ alkyl; CO₂C₃-C₈ cycloalkyl; OCOC₁-C₆        alkyl; OCOC₆-C₁₀ aryl; OCO (5- to 10-membered heteroaryl); OCO        (3- to 7-membered heterocycloalkyl); C₆-C₁₀ aryl; 5- to        10-membered heteroaryl; NH₂; NHC₁-C₆ alkyl; N(C₁-C₆ alkyl)₂;        CONR⁸R⁹; SF₅; and S(O₂)C₁-C₆ alkyl.

In some embodiments of the compound of formula AA,

the substituted ring A is

and R¹ is selected from:

-   -   1-hydroxy-2-methylpropan-2-yl; methyl; isopropyl;        2-hydroxy-2-propyl; hydroxymethyl; 1-hydroxyethyl;        2-hydroxyethyl; 1-hydroxy-2-propyl; 1-hydroxy-1-cyclopropyl;        1-hydroxy-1-cyclobutyl; 1-hydroxy-1-cyclopentyl;        1-hydroxy-1-cyclohexyl; morpholinyl; 1,3-dioxolan-2-yl; COCH₃;        COCH₂CH₃; 2-methoxy-2-propyl; (dimethylamino)methyl;        1-(dimethylamino)ethyl; fluoro; chloro; phenyl; pyridyl;        pyrazolyl; and S(O₂)CH₃.

In some embodiments of the compound of formula AA,

the substituted ring A is

and R¹ is selected from:

-   -   C₁-C₆ alkyl optionally substituted with one or more hydroxy;        C₃-C₇ cycloalkyl optionally substituted with one or more        hydroxy; 3- to 7-membered heterocycloalkyl optionally        substituted with one or more hydroxy; C₁-C₆ alkyl substituted        with one or more oxo; C₃-C₇ cycloalkyl substituted with one or        more oxo; C₁-C₆ alkyl substituted with one or more C₁-C₆ alkoxy;        C₃-C₇ cycloalkyl substituted with one or more C₁-C₆ alkoxy;        C₁-C₆ alkyl substituted with one or more NR⁸R⁹; 3- to 7-membered        heterocycloalkyl substituted with one or more NR⁸R⁹; C₁-C₆        haloalkyl; C₁-C₆ alkoxy; C₁-C₆ haloalkoxy; halo; CN; NO₂;        COC₁-C₆ alkyl; CO—C₆-C₁₀ aryl; CO (5- to 10-membered        heteroaryl); CO₂C₁-C₆ alkyl; CO₂C₃-C₈ cycloalkyl; OCOC₁-C₆        alkyl; OCOC₆-C₁₀ aryl; OCO (5- to 10-membered heteroaryl); OCO        (3- to 7-membered heterocycloalkyl); C₆-C₁₀ aryl; 5- to        10-membered heteroaryl; NH₂; NHC₁-C₆ alkyl; N(C₁-C₆ alkyl)₂;        CONR⁸R⁹; SF₅; and S(O₂)C₁-C₆ alkyl.

In some embodiments of the compound of formula AA,

the substituted ring A is

and R¹ is selected from:

-   -   1-hydroxy-2-methylpropan-2-yl; methyl; isopropyl;        2-hydroxy-2-propyl; hydroxymethyl; 1-hydroxyethyl;        2-hydroxyethyl; 1-hydroxy-2-propyl; 1-hydroxy-1-cyclopropyl;        1-hydroxy-1-cyclobutyl; 1-hydroxy-1-cyclopentyl;        1-hydroxy-1-cyclohexyl; morpholinyl; 1,3-dioxolan-2-yl; COCH₃;        COCH₂CH₃; 2-methoxy-2-propyl; (dimethylamino)methyl;        1-(dimethylamino)ethyl; fluoro; chloro; phenyl; pyridyl;        pyrazolyl; and S(O₂)CH₃.

In some embodiments of the compound of formula AA,

the substituted ring A is

and R¹ is selected from:

-   -   C₁-C₆ alkyl optionally substituted with one or more hydroxy;        C₃-C₇ cycloalkyl optionally substituted with one or more        hydroxy; 3- to 7-membered heterocycloalkyl optionally        substituted with one or more hydroxy; C₁-C₆ alkyl substituted        with one or more oxo; C₃-C₇ cycloalkyl substituted with one or        more oxo; C₁-C₆ alkyl substituted with one or more C₁-C₆ alkoxy;        C₃-C₇ cycloalkyl substituted with one or more C₁-C₆ alkoxy;        C₁-C₆ alkyl substituted with one or more NR⁸R⁹; 3- to 7-membered        heterocycloalkyl substituted with one or more NR⁸R⁹; C₁-C₆        haloalkyl; C₁-C₆ alkoxy; C₁-C₆ haloalkoxy; halo; CN; NO₂;        COC₁-C₆ alkyl; CO—C₆-C₁₀ aryl; CO (5- to 10-membered        heteroaryl); CO₂C₁-C₆ alkyl; CO₂C₃-C₈ cycloalkyl; OCOC₁-C₆        alkyl; OCOC₆-C₁₀ aryl; OCO (5- to 10-membered heteroaryl); OCO        (3- to 7-membered heterocycloalkyl); C₆-C₁₀ aryl; 5- to        10-membered heteroaryl; NH₂; NHC₁-C₆ alkyl; N(C₁-C₆ alkyl)₂;        CONR⁸R⁹; SF₅; and S(O₂)C₁-C₆ alkyl.

In some embodiments of the compound of formula AA,

the substituted ring A is

and R¹ is selected from:

-   -   1-hydroxy-2-methylpropan-2-yl; methyl; isopropyl;        2-hydroxy-2-propyl; hydroxymethyl; 1-hydroxyethyl;        2-hydroxyethyl; 1-hydroxy-2-propyl; 1-hydroxy-1-cyclopropyl;        1-hydroxy-1-cyclobutyl; 1-hydroxy-1-cyclopentyl;        1-hydroxy-1-cyclohexyl; morpholinyl; 1,3-dioxolan-2-yl; COCH₃;        COCH₂CH₃; 2-methoxy-2-propyl; (dimethylamino)methyl;        1-(dimethylamino)ethyl; fluoro; chloro; phenyl; pyridyl;        pyrazolyl; and S(O₂)CH₃.

In some embodiments of the compound of formula AA,

the substituted ring A is

and R¹ is selected from:

-   -   C₁-C₆ alkyl optionally substituted with one or more hydroxy;        C₃-C₇ cycloalkyl optionally substituted with one or more        hydroxy; 3- to 7-membered heterocycloalkyl optionally        substituted with one or more hydroxy; C₁-C₆ alkyl substituted        with one or more oxo; C₃-C₇ cycloalkyl substituted with one or        more oxo; C₁-C₆ alkyl substituted with one or more C₁-C₆ alkoxy;        C₃-C₇ cycloalkyl substituted with one or more C₁-C₆ alkoxy;        C₁-C₆ alkyl substituted with one or more NR⁸R⁹; 3- to 7-membered        heterocycloalkyl substituted with one or more NR⁸R⁹; C₁-C₆        haloalkyl; C₁-C₆ alkoxy; C₁-C₆ haloalkoxy; halo; CN; NO₂;        COC₁-C₆ alkyl; CO—C₆-C₁₀ aryl; CO (5- to 10-membered        heteroaryl); CO₂C₁-C₆ alkyl; CO₂C₃-C₈ cycloalkyl; OCOC₁-C₆        alkyl; OCOC₆-C₁₀ aryl; OCO (5- to 10-membered heteroaryl); OCO        (3- to 7-membered heterocycloalkyl); C₆-C₁₀ aryl; 5- to        10-membered heteroaryl; NH₂; NHC₁-C₆ alkyl; N(C₁-C₆ alkyl)₂;        CONR⁸R⁹; SF₅; and S(O₂)C₁-C₆ alkyl.

In some embodiments of the compound of formula AA,

the substituted ring A is

and R¹ is selected from:

-   -   1-hydroxy-2-methylpropan-2-yl; methyl; isopropyl;        2-hydroxy-2-propyl; hydroxymethyl; 1-hydroxyethyl;        2-hydroxyethyl; 1-hydroxy-2-propyl; 1-hydroxy-1-cyclopropyl;        1-hydroxy-1-cyclobutyl; 1-hydroxy-1-cyclopentyl;        1-hydroxy-1-cyclohexyl; morpholinyl; 1,3-dioxolan-2-yl; COCH₃;        COCH₂CH₃; 2-methoxy-2-propyl; (dimethylamino)methyl;        1-(dimethylamino)ethyl; fluoro; chloro; phenyl; pyridyl;        pyrazolyl; and S(O₂)CH₃.        the substituted ring A is

and R¹ is selected from:

-   -   C₁-C₆ alkyl optionally substituted with one or more hydroxy;        C₃-C₇ cycloalkyl optionally substituted with one or more        hydroxy; 3- to 7-membered heterocycloalkyl optionally        substituted with one or more hydroxy; C₁-C₆ alkyl substituted        with one or more oxo; C₃-C₇ cycloalkyl substituted with one or        more oxo; C₁-C₆ alkyl substituted with one or more C₁-C₆ alkoxy;        C₃-C₇ cycloalkyl substituted with one or more C₁-C₆ alkoxy;        C₁-C₆ alkyl substituted with one or more NR⁸R⁹; 3- to 7-membered        heterocycloalkyl substituted with one or more NR⁸R⁹; C₁-C₆        haloalkyl; C₁-C₆ alkoxy; C₁-C₆ haloalkoxy; halo; CN; NO₂;        COC₁-C₆ alkyl; CO—C₆-C₁₀ aryl; CO (5- to 10-membered        heteroaryl); CO₂C₁-C₆ alkyl; CO₂C₃-C₈ cycloalkyl; OCOC₁-C₆        alkyl; OCOC₆-C₁₀ aryl; OCO (5- to 10-membered heteroaryl); OCO        (3- to 7-membered heterocycloalkyl); C₆-C₁₀ aryl; 5- to        10-membered heteroaryl; NH₂; NHC₁-C₆ alkyl; N(C₁-C₆ alkyl)₂;        CONR⁸R⁹; SF₅; and S(O₂)C₁-C₆ alkyl.

In some embodiments of the compound of formula AA,

the substituted ring A is

and R¹ is selected from:

-   -   1-hydroxy-2-methylpropan-2-yl; methyl; isopropyl;        2-hydroxy-2-propyl; hydroxymethyl; 1-hydroxyethyl;        2-hydroxyethyl; 1-hydroxy-2-propyl; 1-hydroxy-1-cyclopropyl;        1-hydroxy-1-cyclobutyl; 1-hydroxy-1-cyclopentyl;        1-hydroxy-1-cyclohexyl; morpholinyl; 1,3-dioxolan-2-yl; COCH₃;        COCH₂CH₃; 2-methoxy-2-propyl; (dimethylamino)methyl;        1-(dimethylamino)ethyl; fluoro; chloro; phenyl; pyridyl;        pyrazolyl; and S(O₂)CH₃.

In some embodiments of the compound of formula AA,

the substituted ring A is

and R¹ is selected from:

-   -   C₁-C₆ alkyl optionally substituted with one or more hydroxy;        C₃-C₇ cycloalkyl optionally substituted with one or more        hydroxy; 3- to 7-membered heterocycloalkyl optionally        substituted with one or more hydroxy; C₁-C₆ alkyl substituted        with one or more oxo; C₃-C₇ cycloalkyl substituted with one or        more oxo; C₁-C₆ alkyl substituted with one or more C₁-C₆ alkoxy;        C₃-C₇ cycloalkyl substituted with one or more C₁-C₆ alkoxy;        C₁-C₆ alkyl substituted with one or more NR⁸R⁹; 3- to 7-membered        heterocycloalkyl substituted with one or more NR⁸R⁹; C₁-C₆        haloalkyl; C₁-C₆ alkoxy; C₁-C₆ haloalkoxy; halo; CN; NO₂;        COC₁-C₆ alkyl; CO—C₆-C₁₀ aryl; CO-5- to 10-membered heteroaryl;        CO₂C₁-C₆ alkyl; CO₂C₃-C₈ cycloalkyl; OCOC₁-C₆ alkyl; OCOC₆-C₁₀        aryl; OCO (5- to 10-membered heteroaryl); OCO (3- to 7-membered        heterocycloalkyl); C₆-C₁₀ aryl; 5- to 10-membered heteroaryl;        NH₂; NHC₁-C₆ alkyl; N(C₁-C₆ alkyl)₂; CONR⁸R⁹; SF₅; and        S(O₂)C₁-C₆ alkyl.

In some embodiments of the compound of formula AA,

the substituted ring A is

and R¹ is selected from:

-   -   1-hydroxy-2-methylpropan-2-yl; methyl; isopropyl;        2-hydroxy-2-propyl; hydroxymethyl; 1-hydroxyethyl;        2-hydroxyethyl; 1-hydroxy-2-propyl; 1-hydroxy-1-cyclopropyl;        1-hydroxy-1-cyclobutyl; 1-hydroxy-1-cyclopentyl;        1-hydroxy-1-cyclohexyl; morpholinyl; 1,3-dioxolan-2-yl; COCH₃;        COCH₂CH₃; 2-methoxy-2-propyl; (dimethylamino)methyl;        1-(dimethylamino)ethyl; fluoro; chloro; phenyl; pyridyl;        pyrazolyl; and S(O₂)CH₃.

In some embodiments of the compound of formula AA,

the substituted ring A is

and R¹ is selected from:

-   -   C₁-C₆ alkyl optionally substituted with one or more hydroxy;        C₃-C₇ cycloalkyl optionally substituted with one or more        hydroxy; 3- to 7-membered heterocycloalkyl optionally        substituted with one or more hydroxy; C₁-C₆ alkyl substituted        with one or more oxo; C₃-C₇ cycloalkyl substituted with one or        more oxo; C₁-C₆ alkyl substituted with one or more C₁-C₆ alkoxy;        C₃-C₇ cycloalkyl substituted with one or more C₁-C₆ alkoxy;        C₁-C₆ alkyl substituted with one or more NR⁸R⁹; 3- to 7-membered        heterocycloalkyl substituted with one or more NR⁸R⁹; C₁-C₆        haloalkyl; C₁-C₆ alkoxy; C₁-C₆ haloalkoxy; halo; CN; NO₂;        COC₁-C₆ alkyl; CO—C₆-C₁₀ aryl; CO (5- to 10-membered        heteroaryl); CO₂C₁-C₆ alkyl; CO₂C₃-C₈ cycloalkyl; OCOC₁-C₆        alkyl; OCOC₆-C₁₀ aryl; OCO (5- to 10-membered heteroaryl); OCO        (3- to 7-membered heterocycloalkyl); C₆-C₁₀ aryl; 5- to        10-membered heteroaryl; NH₂; NHC₁-C₆ alkyl; N(C₁-C₆ alkyl)₂;        CONR⁸R⁹; SF₅; and S(O₂)C₁-C₆ alkyl.

In some embodiments of the compound of formula AA,

the substituted ring A is

and R¹ is selected from:

-   -   1-hydroxy-2-methylpropan-2-yl; methyl; isopropyl;        2-hydroxy-2-propyl; hydroxymethyl; 1-hydroxyethyl;        2-hydroxyethyl; 1-hydroxy-2-propyl; 1-hydroxy-1-cyclopropyl;        1-hydroxy-1-cyclobutyl; 1-hydroxy-1-cyclopentyl;        1-hydroxy-1-cyclohexyl; morpholinyl; 1,3-dioxolan-2-yl; COCH₃;        COCH₂CH₃; 2-methoxy-2-propyl; (dimethylamino)methyl;        1-(dimethylamino)ethyl; fluoro; chloro; phenyl; pyridyl;        pyrazolyl; and S(O₂)CH₃.

In some embodiments of the compound of formula AA,

the substituted ring A is

and R¹ is selected from:

-   -   C₁-C₆ alkyl optionally substituted with one or more hydroxy;        C₃-C₇ cycloalkyl optionally substituted with one or more        hydroxy; 3- to 7-membered heterocycloalkyl optionally        substituted with one or more hydroxy; C₁-C₆ alkyl substituted        with one or more oxo; C₃-C₇ cycloalkyl substituted with one or        more oxo; C₁-C₆ alkyl substituted with one or more C₁-C₆ alkoxy;        C₃-C₇ cycloalkyl substituted with one or more C₁-C₆ alkoxy;        C₁-C₆ haloalkyl; C₁-C₆ alkoxy; C₁-C₆ haloalkoxy; halo; CN; NO₂;        COC₁-C₆ alkyl; CO—C₆-C₁₀ aryl; CO (5- to 10-membered        heteroaryl); CO₂C₁-C₆ alkyl; CO₂C₃-C₈ cycloalkyl; OCOC₁-C₆        alkyl; OCOC₆-C₁₀ aryl; OCO (5- to 10-membered heteroaryl); OCO        (3- to 7-membered heterocycloalkyl); C₆-C₁₀ aryl; 5- to        10-membered heteroaryl; NH₂; NHC₁-C₆ alkyl; N(C₁-C₆ alkyl)₂;        CONR⁸R⁹; SF₅; C₁-C₆ alkyl substituted with one or more NR⁸R⁹;        and S(O₂)C₁-C₆ alkyl.        the substituted ring A is

and R¹ is selected from:

-   -   1-hydroxy-2-methylpropan-2-yl; methyl; isopropyl;        2-hydroxy-2-propyl; hydroxymethyl; 1-hydroxyethyl;        2-hydroxyethyl; 1-hydroxy-2-propyl; 1-hydroxy-1-cyclopropyl;        1-hydroxy-1-cyclobutyl; 1-hydroxy-1-cyclopentyl;        1-hydroxy-1-cyclohexyl; morpholinyl;    -   (dimethylamino)methyl; 1,3-dioxolan-2-yl; COCH₃; COCH₂CH₃;        2-methoxy-2-propyl; fluoro; chloro; phenyl; pyridyl; pyrazolyl;        and S(O₂)CH₃.        the substituted ring A is

and R¹ is selected from:

-   -   C₁-C₆ alkyl optionally substituted with one or more hydroxy;        C₃-C₇ cycloalkyl optionally substituted with one or more        hydroxy; 3- to 7-membered heterocycloalkyl optionally        substituted with one or more hydroxy; C₁-C₆ alkyl substituted        with one or more oxo; C₃—C₇ cycloalkyl substituted with one or        more oxo; C₁-C₆ alkyl substituted with one or more C₁-C₆ alkoxy;        C₃-C₇ cycloalkyl substituted with one or more C₁-C₆ alkoxy;        C₁-C₆ haloalkyl; C₁-C₆ alkoxy; C₁-C₆ haloalkoxy; halo; CN; NO₂;        COC₁-C₆ alkyl; CO—C₆-C₁₀ aryl; CO (5- to 10-membered        heteroaryl); CO₂C₁-C₆ alkyl; CO₂C₃-C₈ cycloalkyl; OCOC₁-C₆        alkyl; OCOC₆-C₁₀ aryl; OCO (5- to 10-membered heteroaryl); OCO        (3- to 7-membered heterocycloalkyl); C₆-C₁₀ aryl; 5- to        10-membered heteroaryl; NH₂; NHC₁-C₆ alkyl; N(C₁-C₆ alkyl)₂;        CONR⁸R⁹; SF₅; C₁-C₆ alkyl substituted with one or more NR⁸R⁹;        and S(O₂)C₁-C₆ alkyl.        the substituted ring A is

and R¹ is selected from:

-   -   1-hydroxy-2-methylpropan-2-yl; methyl; isopropyl;        2-hydroxy-2-propyl; hydroxymethyl; 1-hydroxyethyl;        2-hydroxyethyl; 1-hydroxy-2-propyl; 1-hydroxy-1-cyclopropyl;        1-hydroxy-1-cyclobutyl; 1-hydroxy-1-cyclopentyl;        1-hydroxy-1-cyclohexyl; morpholinyl; 1,3-dioxolan-2-yl; COCH₃;        COCH₂CH₃; 2-methoxy-2-propyl; fluoro; chloro; phenyl; pyridyl;        pyrazolyl; (dimethylamino)methyl; and S(O₂)CH₃.

In some embodiments of the compound of formula AA,

the substituted ring A is

and R¹ and R² are one of the following combinations:

-   -   R¹ is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R² is C₁-C₆ alkyl optionally substituted with one        or more hydroxy;    -   R¹ is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R² is C₆-C₁₀ aryl;    -   R¹ is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R² is 5- to 10-membered heteroaryl;    -   R¹ is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R² is SF₅;    -   R¹ is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R² is S(O₂)C₁-C₆ alkyl;    -   R¹ is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R² is halo;

R¹ is C₃-C₇ cycloalkyl optionally substituted with one or more hydroxy,and R² is C₁-C₆ alkyl;

R¹ is 3- to 7-membered heterocycloalkyl optionally substituted with oneor more hydroxy, and R² is C₁-C₆ alkyl;

R¹ is 3- to 7-membered heterocycloalkyl optionally substituted with oneor more hydroxy, and R² is halo;

-   -   R¹ is C₁-C₆ alkyl optionally substituted with one or more oxo,        and R² is methyl;    -   R¹ is C₁-C₆ alkyl optionally substituted with one or more C₁-C₆        alkoxy, and R² is C₁-C₆ alkyl;    -   R¹ is C₁-C₆ alkyl optionally substituted with one or more NR⁸R⁹,        and R² is C₁-C₆ alkyl;    -   R¹ is C₁-C₆ alkyl optionally substituted with one or more NR⁸R⁹,        and R² is halo;    -   R² is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R¹ is C₆-C₁₀ aryl;    -   R² is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R¹ is 5- to 10-membered heteroaryl;    -   R² is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R¹ is SF₅.    -   R² is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R¹ is S(O₂)C₁-C₆ alkyl;    -   R² is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R¹ is halo;    -   R² is C₃-C₇ cycloalkyl optionally substituted with one or more        hydroxy, and R¹ is C₁-C₆ alkyl;    -   R² is 3- to 7-membered heterocycloalkyl optionally substituted        with one or more hydroxy, and R¹ is C₁-C₆ alkyl;    -   R² is 3- to 7-membered heterocycloalkyl optionally substituted        with one or more hydroxy, and R¹ is halo;    -   R² is C₁-C₆ alkyl optionally substituted with one or more oxo,        and R¹ is methyl;    -   R² is C₁-C₆ alkyl optionally substituted with one or more C₁-C₆        alkoxy, and R¹ is C₁-C₆ alkyl;    -   R² is C₁-C₆ alkyl optionally substituted with one or more NR⁸R⁹,        and R¹ is C₁-C₆ alkyl;    -   R² is C₁-C₆ alkyl optionally substituted with one or more NR⁸R⁹,        and R¹ is halo.

In some embodiments of the compound of formula AA,

the substituted ring A is

and R¹ and R² are one of the following combinations:

-   -   R¹ is 1-hydroxy-2-methylpropan-2-yl, and R² is methyl;    -   R¹ is 2-hydroxy-2-propyl and R² is methyl;    -   R¹ is 2-hydroxy-2-propyl and R² is isopropyl;    -   R¹ is 2-hydroxy-2-propyl and R² is 2-hydroxy-2-propyl;    -   R¹ is 2-hydroxy-2-propyl and R² is 1-hydroxyethyl;    -   R¹ is hydroxymethyl and R² is methyl;    -   R¹ is 1-hydroxyethyl and R² is methyl;    -   R¹ is 2-hydroxyethyl and R² is methyl;    -   R¹ is 1-hydroxy-2-propyl and R² is methyl;    -   R¹ is 2-hydroxy-2-propyl and R² is phenyl;    -   R¹ is 2-hydroxy-2-propyl and R² is pyridyl;    -   R¹ is 2-hydroxy-2-propyl and R² is pyrazolyl;    -   R¹ is 2-hydroxy-2-propyl, and R² is S(O₂)CH₃;    -   R¹ is 2-hydroxy-2-propyl and R² is chloro;    -   R¹ is 2-hydroxy-2-propyl and R² is fluoro;    -   R¹ is 1-hydroxy-1-cyclopropyl, and R² is methyl;    -   R¹ is 1-hydroxy-1-cyclobutyl, and R² is methyl;    -   R¹ is 1-hydroxy-1-cyclopentyl, and R² is methyl;    -   R¹ is 1-hydroxy-1-cyclohexyl, and R² is methyl;    -   R¹ is morpholinyl, and R² is methyl;    -   R¹ is 1,3-dioxolan-2-yl, and R² is methyl;    -   R¹ is 1,3-dioxolan-2-yl, and R² is fluoro;    -   R¹ is 1,3-dioxolan-2-yl, and R² is chloro;    -   R¹ is COCH₃, and R² is methyl;    -   R¹ is 2-methoxy-2-propyl, and R² is methyl;    -   R² is (dimethylamino)methyl, and R¹ is methyl.    -   R² is 1-hydroxy-2-methylpropan-2-yl, and R¹ is methyl;    -   R² is 2-hydroxy-2-propyl and R¹ is methyl;    -   R² is 2-hydroxy-2-propyl and R¹ is isopropyl;    -   R² is 2-hydroxy-2-propyl and R¹ is 1-hydroxyethyl;    -   R² is hydroxymethyl and R¹ is methyl;    -   R² is 1-hydroxyethyl and R¹ is methyl;    -   R² is 2-hydroxyethyl and R¹ is methyl;    -   R² is 1-hydroxy-2-propyl and R¹ is methyl;    -   R² is 2-hydroxy-2-propyl and R¹ is phenyl;    -   R² is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R¹ is 5- to 10-membered heteroaryl;    -   R² is 2-hydroxy-2-propyl and R¹ is pyridyl;    -   R² is 2-hydroxy-2-propyl and R¹ is pyrazolyl;    -   R² is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R¹ is S(O₂)CH₃;    -   R² is 2-hydroxy-2-propyl and R¹ is chloro;    -   R² is 2-hydroxy-2-propyl and R¹ is fluoro;    -   R² is C₃-C₇ cycloalkyl optionally substituted with one or more        hydroxy, and R¹ is C₁-C₆ alkyl;    -   R² is 1-hydroxy-1-cyclopropyl, and R¹ is methyl;    -   R² is 1-hydroxy-1-cyclobutyl, and R¹ is methyl;    -   R² is 1-hydroxy-1-cyclopentyl, and R¹ is methyl;    -   R² is 1-hydroxy-1-cyclohexyl, and R¹ is methyl;    -   R² is morpholinyl, and R¹ is methyl;    -   R² is 1,3-dioxolan-2-yl, and R¹ is methyl;    -   R² is 1,3-dioxolan-2-yl, and R¹ is fluoro;    -   R² is 1,3-dioxolan-2-yl, and R¹ is chloro;    -   R² is C₁-C₆ alkyl optionally substituted with one or more oxo,        and R¹ is methyl;    -   R² is COCH₃, and R¹ is methyl; or    -   R² is 2-methoxy-2-propyl, and R¹ is methyl.

In some embodiments, of the compound of formula AA,

the substituted ring A is

and R¹ and R² are one of the following combinations:

-   -   R¹ is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R² is C₁-C₆ alkyl optionally substituted with one        or more hydroxy;    -   R¹ is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R² is C₆-C₁₀ aryl;    -   R¹ is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R² is 5- to 10-membered heteroaryl;    -   R¹ is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R² is SF₅;    -   R¹ is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R² is S(O₂)C₁-C₆ alkyl;    -   R¹ is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R² is halo;    -   R¹ is C₃-C₇ cycloalkyl optionally substituted with one or more        hydroxy, and R² is C₁-C₆ alkyl;    -   R¹ is 3- to 7-membered heterocycloalkyl optionally substituted        with one or more hydroxy, and R² is C₁-C₆ alkyl;    -   R¹ is 3- to 7-membered heterocycloalkyl optionally substituted        with one or more hydroxy, and R² is halo;    -   R¹ is C₁-C₆ alkyl optionally substituted with one or more oxo,        and R² is methyl;    -   R¹ is C₁-C₆ alkyl optionally substituted with one or more C₁-C₆        alkoxy, and R² is C₁-C₆ alkyl;    -   R¹ is C₁-C₆ alkyl optionally substituted with one or more NR⁸R⁹,        and R² is C₁-C₆ alkyl;    -   R¹ is C₁-C₆ alkyl optionally substituted with one or more NR⁸R⁹,        and R² is halo;    -   R² is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R¹ is C₆-C₁₀ aryl;    -   R² is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R¹ is 5- to 10-membered heteroaryl;    -   R² is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R¹ is SF₅.    -   R² is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R¹ is S(O₂)C₁-C₆ alkyl;    -   R² is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R¹ is halo;    -   R² is C₃-C₇ cycloalkyl optionally substituted with one or more        hydroxy, and R¹ is C₁-C₆ alkyl;    -   R² is 3- to 7-membered heterocycloalkyl optionally substituted        with one or more hydroxy, and R¹ is C₁-C₆ alkyl;    -   R² is 3- to 7-membered heterocycloalkyl optionally substituted        with one or more hydroxy, and R¹ is halo;    -   R² is C₁-C₆ alkyl optionally substituted with one or more oxo,        and R¹ is methyl;        -   or    -   R² is C₁-C₆ alkyl optionally substituted with one or more C₁-C₆        alkoxy, and R¹ is C₁-C₆ alkyl.    -   R² is C₁-C₆ alkyl optionally substituted with one or more NR⁸R⁹,        and R¹ is C₁-C₆ alkyl;        -   or    -   R² is C₁-C₆ alkyl optionally substituted with one or more NR⁸R⁹,        and R¹ is halo.

In some embodiments, of the compound of formula AA,

the substituted ring A is

and R¹ and R² are one of the following combinations:

-   -   R¹ is 1-hydroxy-2-methylpropan-2-yl, and R² is methyl;    -   R¹ is 2-hydroxy-2-propyl and R² is methyl;    -   R¹ is 2-hydroxy-2-propyl and R² is isopropyl;    -   R¹ is 2-hydroxy-2-propyl and R² is 2-hydroxy-2-propyl;    -   R¹ is 2-hydroxy-2-propyl and R² is 1-hydroxyethyl;    -   R¹ is hydroxymethyl and R² is methyl;    -   R¹ is 1-hydroxyethyl and R² is methyl;    -   R¹ is 2-hydroxyethyl and R² is methyl;    -   R¹ is 1-hydroxy-2-propyl and R² is methyl;    -   R¹ is 2-hydroxy-2-propyl and R² is phenyl;    -   R¹ is 2-hydroxy-2-propyl and R² is pyridyl;    -   R¹ is 2-hydroxy-2-propyl and R² is pyrazolyl;    -   R¹ is 2-hydroxy-2-propyl, and R² is S(O₂)CH₃;    -   R¹ is 2-hydroxy-2-propyl and R² is chloro;    -   R¹ is 2-hydroxy-2-propyl and R² is fluoro;    -   R¹ is 1-hydroxy-1-cyclopropyl, and R² is methyl;    -   R¹ is 1-hydroxy-1-cyclobutyl, and R² is methyl;    -   R¹ is 1-hydroxy-1-cyclopentyl, and R² is methyl;    -   R¹ is 1-hydroxy-1-cyclohexyl, and R² is methyl;    -   R¹ is morpholinyl, and R² is methyl;    -   R¹ is 1,3-dioxolan-2-yl, and R² is methyl;    -   R¹ is 1,3-dioxolan-2-yl, and R² is fluoro;    -   R¹ is 1,3-dioxolan-2-yl, and R² is chloro;    -   R¹ is COCH₃, and R² is methyl;    -   R¹ is 2-methoxy-2-propyl, and R² is methyl;    -   R¹ is (dimethylamino)methyl, and R² is methyl.    -   R² is 1-hydroxy-2-methylpropan-2-yl, and R¹ is methyl;    -   R² is 2-hydroxy-2-propyl and R¹ is methyl;    -   R² is 2-hydroxy-2-propyl and R¹ is isopropyl;    -   R² is 2-hydroxy-2-propyl and R¹ is 1-hydroxyethyl;    -   R² is hydroxymethyl and R¹ is methyl;    -   R² is 1-hydroxyethyl and R¹ is methyl;    -   R² is 2-hydroxyethyl and R¹ is methyl;    -   R² is 1-hydroxy-2-propyl and R¹ is methyl;    -   R² is 2-hydroxy-2-propyl and R¹ is phenyl;    -   R² is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R¹ is 5- to 10-membered heteroaryl;    -   R² is 2-hydroxy-2-propyl and R¹ is pyridyl;    -   R² is 2-hydroxy-2-propyl and R¹ is pyrazolyl;    -   R² is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R¹ is S(O₂)CH₃;    -   R² is 2-hydroxy-2-propyl and R¹ is chloro;    -   R² is 2-hydroxy-2-propyl and R¹ is fluoro;    -   R² is C₃-C₇ cycloalkyl optionally substituted with one or more        hydroxy, and R¹ is C₁-C₆ alkyl;    -   R² is 1-hydroxy-1-cyclopropyl, and R¹ is methyl;    -   R² is 1-hydroxy-1-cyclobutyl, and R¹ is methyl;    -   R² is 1-hydroxy-1-cyclopentyl, and R¹ is methyl;    -   R² is 1-hydroxy-1-cyclohexyl, and R¹ is methyl;    -   R² is morpholinyl, and R¹ is methyl;    -   R² is 1,3-dioxolan-2-yl, and R¹ is methyl;    -   R² is 1,3-dioxolan-2-yl, and R¹ is fluoro;    -   R² is 1,3-dioxolan-2-yl, and R¹ is chloro;    -   R² is C₁-C₆ alkyl optionally substituted with one or more oxo,        and R¹ is methyl;    -   R² is (dimethylamino)methyl, and R¹ is methyl;    -   R² is COCH₃, and R¹ is methyl; or    -   R² is 2-methoxy-2-propyl, and R¹ is methyl.

In some embodiments, of the compound of formula AA,

the substituted ring A is

and R¹ and R² are one of the following combinations:

-   -   R¹ is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R² is C₁-C₆ alkyl optionally substituted with one        or more hydroxy;    -   R¹ is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R² is C₆-C₁₀ aryl;    -   R¹ is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R² is 5- to 10-membered heteroaryl;    -   R¹ is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R² is SF₅;    -   R¹ is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R² is S(O₂)C₁-C₆ alkyl;    -   R¹ is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R² is halo;    -   R¹ is C₃-C₇ cycloalkyl optionally substituted with one or more        hydroxy, and R² is C₁-C₆ alkyl;    -   R¹ is 3- to 7-membered heterocycloalkyl optionally substituted        with one or more hydroxy, and R² is C₁-C₆ alkyl;    -   R¹ is 3- to 7-membered heterocycloalkyl optionally substituted        with one or more hydroxy, and R² is halo;    -   R¹ is C₁-C₆ alkyl optionally substituted with one or more oxo,        and R² is methyl;    -   R¹ is C₁-C₆ alkyl optionally substituted with one or more C₁-C₆        alkoxy, and R² is C₁-C₆ alkyl;    -   R¹ is C₁-C₆ alkyl optionally substituted with one or more NR⁸R⁹,        and R² is C₁-C₆ alkyl;    -   R¹ is C₁-C₆ alkyl optionally substituted with one or more NR⁸R⁹,        and R² is halo;    -   R² is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R¹ is C₆-C₁₀ aryl;    -   R² is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R¹ is 5- to 10-membered heteroaryl;    -   R² is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R¹ is SF₅.    -   R² is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R¹ is S(O₂)C₁-C₆ alkyl;    -   R² is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R¹ is halo;    -   R² is C₃-C₇ cycloalkyl optionally substituted with one or more        hydroxy, and R¹ is C₁-C₆ alkyl;    -   R² is 3- to 7-membered heterocycloalkyl optionally substituted        with one or more hydroxy, and R¹ is C₁-C₆ alkyl;    -   R² is 3- to 7-membered heterocycloalkyl optionally substituted        with one or more hydroxy, and R¹ is halo;    -   R² is C₁-C₆ alkyl optionally substituted with one or more NR⁸R⁹,        and R¹ is C₁-C₆ alkyl;    -   R² is C₁-C₆ alkyl optionally substituted with one or more NR⁸R⁹,        and R¹ is halo;    -   R² is C₁-C₆ alkyl optionally substituted with one or more oxo,        and R¹ is methyl; or    -   R² is C₁-C₆ alkyl optionally substituted with one or more C₁-C₆        alkoxy, and R¹ is C₁-C₆ alkyl.

In some embodiments, of the compound of formula AA,

the substituted ring A is

and R¹ and R² are one of the following combinations:

-   -   R¹ is 1-hydroxy-2-methylpropan-2-yl, and R² is methyl;    -   R¹ is 2-hydroxy-2-propyl and R² is methyl;    -   R¹ is 2-hydroxy-2-propyl and R² is isopropyl;    -   R¹ is 2-hydroxy-2-propyl and R² is 2-hydroxy-2-propyl;    -   R¹ is 2-hydroxy-2-propyl and R² is 1-hydroxyethyl;    -   R¹ is hydroxymethyl and R² is methyl;    -   R¹ is 1-hydroxyethyl and R² is methyl;    -   R¹ is 2-hydroxyethyl and R² is methyl;    -   R¹ is 1-hydroxy-2-propyl and R² is methyl;    -   R¹ is 2-hydroxy-2-propyl and R² is phenyl;    -   R¹ is 2-hydroxy-2-propyl and R² is pyridyl;    -   R¹ is 2-hydroxy-2-propyl and R² is pyrazolyl;    -   R¹ is 2-hydroxy-2-propyl, and R² is S(O₂)CH₃;    -   R¹ is 2-hydroxy-2-propyl and R² is chloro;    -   R¹ is 2-hydroxy-2-propyl and R² is fluoro;    -   R¹ is 1-hydroxy-1-cyclopropyl, and R² is methyl;    -   R¹ is 1-hydroxy-1-cyclobutyl, and R² is methyl;    -   R¹ is 1-hydroxy-1-cyclopentyl, and R² is methyl;    -   R¹ is 1-hydroxy-1-cyclohexyl, and R² is methyl;    -   R¹ is morpholinyl, and R² is methyl;    -   R¹ is 1,3-dioxolan-2-yl, and R² is methyl;    -   R¹ is 1,3-dioxolan-2-yl, and R² is fluoro;    -   R¹ is 1,3-dioxolan-2-yl, and R² is chloro;    -   R¹ is COCH₃, and R² is methyl;    -   R¹ is 2-methoxy-2-propyl, and R² is methyl;    -   R¹ is (dimethylamino)methyl, and R² is methyl;    -   R² is 1-hydroxy-2-methylpropan-2-yl, and R¹ is methyl;    -   R² is 2-hydroxy-2-propyl and R¹ is methyl;    -   R² is 2-hydroxy-2-propyl and R¹ is isopropyl;    -   R² is 2-hydroxy-2-propyl and R¹ is 1-hydroxyethyl;    -   R² is hydroxymethyl and R¹ is methyl;    -   R² is 1-hydroxyethyl and R¹ is methyl;    -   R² is 2-hydroxyethyl and R¹ is methyl;    -   R² is 1-hydroxy-2-propyl and R¹ is methyl;    -   R² is 2-hydroxy-2-propyl and R¹ is phenyl;    -   R² is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R¹ is 5- to 10-membered heteroaryl;    -   R² is 2-hydroxy-2-propyl and R¹ is pyridyl;    -   R² is 2-hydroxy-2-propyl and R¹ is pyrazolyl;    -   R² is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R¹ is S(O₂)CH₃;    -   R² is 2-hydroxy-2-propyl and R¹ is chloro;    -   R² is 2-hydroxy-2-propyl and R¹ is fluoro;    -   R² is C₃-C₇ cycloalkyl optionally substituted with one or more        hydroxy, and R¹ is C₁-C₆ alkyl;    -   R² is 1-hydroxy-1-cyclopropyl, and R¹ is methyl;    -   R² is 1-hydroxy-1-cyclobutyl, and R¹ is methyl;    -   R² is 1-hydroxy-1-cyclopentyl, and R¹ is methyl;    -   R² is 1-hydroxy-1-cyclohexyl, and R¹ is methyl;    -   R² is morpholinyl, and R¹ is methyl;    -   R² is 1,3-dioxolan-2-yl, and R¹ is methyl;    -   R² is 1,3-dioxolan-2-yl, and R¹ is fluoro;    -   R² is 1,3-dioxolan-2-yl, and R¹ is chloro;    -   R² is C₁-C₆ alkyl optionally substituted with one or more oxo,        and R¹ is methyl;    -   R² is (dimethylamino)methyl, and R¹ is methyl;    -   R² is COCH₃, and R¹ is methyl; or    -   R² is 2-methoxy-2-propyl, and R¹ is methyl.

In some embodiments, of the compound of formula AA,

the substituted ring A is

and R¹ and R² are one of the following combinations:

-   -   R¹ is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R² is C₁-C₆ alkyl optionally substituted with one        or more hydroxy;    -   R¹ is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R² is C₆-C₁₀ aryl;    -   R¹ is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R² is 5- to 10-membered heteroaryl;    -   R¹ is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R² is SF₅;    -   R¹ is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R² is S(O₂)C₁-C₆ alkyl;    -   R¹ is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R² is halo;    -   R¹ is C₃-C₇ cycloalkyl optionally substituted with one or more        hydroxy, and R² is C₁-C₆ alkyl;    -   R¹ is 3- to 7-membered heterocycloalkyl optionally substituted        with one or more hydroxy, and R² is C₁-C₆ alkyl;    -   R¹ is 3- to 7-membered heterocycloalkyl optionally substituted        with one or more hydroxy, and R² is halo;    -   R¹ is C₁-C₆ alkyl optionally substituted with one or more oxo,        and R² is methyl;    -   R¹ is C₁-C₆ alkyl optionally substituted with one or more C₁-C₆        alkoxy, and R² is C₁-C₆ alkyl;    -   R¹ is C₁-C₆ alkyl optionally substituted with one or more NR⁸R⁹,        and R² is C₁-C₆ alkyl;    -   R¹ is C₁-C₆ alkyl optionally substituted with one or more NR⁸R⁹,        and R² is halo;    -   R² is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R¹ is C₆-C₁₀ aryl;    -   R² is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R¹ is 5- to 10-membered heteroaryl;    -   R² is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R¹ is SF₅.    -   R² is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R¹ is S(O₂)C₁-C₆ alkyl;    -   R² is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R¹ is halo;    -   R² is C₃-C₇ cycloalkyl optionally substituted with one or more        hydroxy, and R¹ is C₁-C₆ alkyl;    -   R² is 3- to 7-membered heterocycloalkyl optionally substituted        with one or more hydroxy, and R¹ is C₁-C₆ alkyl;    -   R² is 3- to 7-membered heterocycloalkyl optionally substituted        with one or more hydroxy, and R¹ is halo;    -   R² is C₁-C₆ alkyl optionally substituted with one or more NR⁸R⁹,        and R¹ is C₁-C₆ alkyl;    -   R² is C₁-C₆ alkyl optionally substituted with one or more NR⁸R⁹,        and R¹ is halo;    -   R² is C₁-C₆ alkyl optionally substituted with one or more oxo,        and R¹ is methyl; or    -   R² is C₁-C₆ alkyl optionally substituted with one or more C₁-C₆        alkoxy, and R¹ is C₁-C₆ alkyl.

In some embodiments, of the compound of formula AA,

the substituted ring A is

and R¹ and R² are one of the following combinations:

-   -   R¹ is 1-hydroxy-2-methylpropan-2-yl, and R² is methyl;    -   R¹ is 2-hydroxy-2-propyl and R² is methyl;    -   R¹ is 2-hydroxy-2-propyl and R² is isopropyl;    -   R¹ is 2-hydroxy-2-propyl and R² is 2-hydroxy-2-propyl;    -   R¹ is 2-hydroxy-2-propyl and R² is 1-hydroxyethyl;    -   R¹ is hydroxymethyl and R² is methyl;    -   R¹ is 1-hydroxyethyl and R² is methyl;    -   R¹ is 2-hydroxyethyl and R² is methyl;    -   R¹ is 1-hydroxy-2-propyl and R² is methyl;    -   R¹ is 2-hydroxy-2-propyl and R² is phenyl;    -   R¹ is 2-hydroxy-2-propyl and R² is pyridyl;    -   R¹ is 2-hydroxy-2-propyl and R² is pyrazolyl;    -   R¹ is 2-hydroxy-2-propyl, and R² is S(O₂)CH₃;    -   R¹ is 2-hydroxy-2-propyl and R² is chloro;    -   R¹ is 2-hydroxy-2-propyl and R² is fluoro;    -   R¹ is 1-hydroxy-1-cyclopropyl, and R² is methyl;    -   R¹ is 1-hydroxy-1-cyclobutyl, and R² is methyl;    -   R¹ is 1-hydroxy-1-cyclopentyl, and R² is methyl;    -   R¹ is 1-hydroxy-1-cyclohexyl, and R² is methyl;    -   R¹ is morpholinyl, and R² is methyl;    -   R¹ is 1,3-dioxolan-2-yl, and R² is methyl;    -   R¹ is 1,3-dioxolan-2-yl, and R² is fluoro;    -   R¹ is 1,3-dioxolan-2-yl, and R² is chloro;    -   R¹ is COCH₃, and R² is methyl;    -   R¹ is 2-methoxy-2-propyl, and R² is methyl;    -   R¹ is (dimethylamino)methyl, and R² is methyl.    -   R² is 1-hydroxy-2-methylpropan-2-yl, and R¹ is methyl;    -   R² is 2-hydroxy-2-propyl and R¹ is methyl;    -   R² is 2-hydroxy-2-propyl and R¹ is isopropyl;    -   R² is 2-hydroxy-2-propyl and R¹ is 1-hydroxyethyl;    -   R² is hydroxymethyl and R¹ is methyl;    -   R² is 1-hydroxyethyl and R¹ is methyl;    -   R² is 2-hydroxyethyl and R¹ is methyl;    -   R² is 1-hydroxy-2-propyl and R¹ is methyl;    -   R² is 2-hydroxy-2-propyl and R¹ is phenyl;    -   R² is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R¹ is 5- to 10-membered heteroaryl;    -   R² is 2-hydroxy-2-propyl and R¹ is pyridyl;    -   R² is 2-hydroxy-2-propyl and R¹ is pyrazolyl;    -   R² is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R¹ is S(O₂)CH₃;    -   R² is 2-hydroxy-2-propyl and R¹ is chloro;    -   R² is 2-hydroxy-2-propyl and R¹ is fluoro;    -   R² is C₃-C₇ cycloalkyl optionally substituted with one or more        hydroxy, and R¹ is C₁-C₆ alkyl;    -   R² is 1-hydroxy-1-cyclopropyl, and R¹ is methyl;    -   R² is 1-hydroxy-1-cyclobutyl, and R¹ is methyl;    -   R² is 1-hydroxy-1-cyclopentyl, and R¹ is methyl;    -   R² is 1-hydroxy-1-cyclohexyl, and R¹ is methyl;    -   R² is morpholinyl, and R¹ is methyl;    -   R² is 1,3-dioxolan-2-yl, and R¹ is methyl;    -   R² is 1,3-dioxolan-2-yl, and R¹ is fluoro;    -   R² is 1,3-dioxolan-2-yl, and R¹ is chloro;    -   R² is C₁-C₆ alkyl optionally substituted with one or more oxo,        and R¹ is methyl;    -   R² is (dimethylamino)methyl, and R¹ is methyl;    -   R² is COCH₃, and R¹ is methyl; or    -   R² is 2-methoxy-2-propyl, and R¹ is methyl.

In some embodiments, of the compound of formula AA,

the substituted ring A is

and R¹ and R² are one of the following combinations:

-   -   R¹ is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R² is C₁-C₆ alkyl optionally substituted with one        or more hydroxy;    -   R¹ is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R² is C₆-C₁₀ aryl;    -   R¹ is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R² is 5- to 10-membered heteroaryl;    -   R¹ is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R² is SF₅;    -   R¹ is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R² is S(O₂)C₁-C₆ alkyl;    -   R¹ is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R² is halo;    -   R¹ is C₃-C₇ cycloalkyl optionally substituted with one or more        hydroxy, and R² is C₁-C₆ alkyl;    -   R¹ is 3- to 7-membered heterocycloalkyl optionally substituted        with one or more hydroxy, and R² is C₁-C₆ alkyl;    -   R¹ is 3- to 7-membered heterocycloalkyl optionally substituted        with one or more hydroxy, and R² is halo;    -   R¹ is C₁-C₆ alkyl optionally substituted with one or more oxo,        and R² is methyl;    -   R¹ is C₁-C₆ alkyl optionally substituted with one or more C₁-C₆        alkoxy, and R² is C₁-C₆ alkyl;    -   R¹ is C₁-C₆ alkyl optionally substituted with one or more NR⁸R⁹,        and R² is C₁-C₆ alkyl;    -   R¹ is C₁-C₆ alkyl optionally substituted with one or more NR⁸R⁹,        and R² is halo;    -   R² is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R¹ is C₆-C₁₀ aryl;    -   R² is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R¹ is 5- to 10-membered heteroaryl;    -   R² is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R¹ is SF₅.    -   R² is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R¹ is S(O₂)C₁-C₆ alkyl;    -   R² is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R¹ is halo;    -   R² is C₃-C₇ cycloalkyl optionally substituted with one or more        hydroxy, and R¹ is C₁-C₆ alkyl;    -   R² is 3- to 7-membered heterocycloalkyl optionally substituted        with one or more hydroxy, and R¹ is C₁-C₆ alkyl;    -   R² is 3- to 7-membered heterocycloalkyl optionally substituted        with one or more hydroxy, and R¹ is halo;    -   R² is C₁-C₆ alkyl optionally substituted with one or more NR⁸R⁹,        and R¹ is C₁-C₆ alkyl;    -   R² is C₁-C₆ alkyl optionally substituted with one or more NR⁸R⁹,        and R¹ is halo;    -   R² is C₁-C₆ alkyl optionally substituted with one or more oxo,        and R¹ is methyl; or    -   R² is C₁-C₆ alkyl optionally substituted with one or more C₁-C₆        alkoxy, and R¹ is C₁-C₆ alkyl.

In some embodiments, of the compound of formula AA,

the substituted ring A is

and R¹ and R² are one of the following combinations:

-   -   R¹ is 1-hydroxy-2-methylpropan-2-yl, and R² is methyl;    -   R¹ is 2-hydroxy-2-propyl and R² is methyl;    -   R¹ is 2-hydroxy-2-propyl and R² is isopropyl;    -   R¹ is 2-hydroxy-2-propyl and R² is 2-hydroxy-2-propyl;    -   R¹ is 2-hydroxy-2-propyl and R² is 1-hydroxyethyl;    -   R¹ is hydroxymethyl and R² is methyl;    -   R¹ is 1-hydroxyethyl and R² is methyl;    -   R¹ is 2-hydroxyethyl and R² is methyl;    -   R¹ is 1-hydroxy-2-propyl and R² is methyl;    -   R¹ is 2-hydroxy-2-propyl and R² is phenyl;    -   R¹ is 2-hydroxy-2-propyl and R² is pyridyl;    -   R¹ is 2-hydroxy-2-propyl and R² is pyrazolyl;    -   R¹ is 2-hydroxy-2-propyl, and R² is S(O₂)CH₃;    -   R¹ is 2-hydroxy-2-propyl and R² is chloro;    -   R¹ is 2-hydroxy-2-propyl and R² is fluoro;    -   R¹ is 1-hydroxy-1-cyclopropyl, and R² is methyl;    -   R¹ is 1-hydroxy-1-cyclobutyl, and R² is methyl;    -   R¹ is 1-hydroxy-1-cyclopentyl, and R² is methyl;    -   R¹ is 1-hydroxy-1-cyclohexyl, and R² is methyl;    -   R¹ is morpholinyl, and R² is methyl;    -   R¹ is 1,3-dioxolan-2-yl, and R² is methyl;    -   R¹ is 1,3-dioxolan-2-yl, and R² is fluoro;    -   R¹ is 1,3-dioxolan-2-yl, and R² is chloro;    -   R¹ is COCH₃, and R² is methyl;    -   R¹ is 2-methoxy-2-propyl, and R² is methyl;    -   R¹ is (dimethylamino)methyl, and R² is methyl.    -   R² is 1-hydroxy-2-methylpropan-2-yl, and R¹ is methyl;    -   R² is 2-hydroxy-2-propyl and R¹ is methyl;    -   R² is 2-hydroxy-2-propyl and R¹ is isopropyl;    -   R² is 2-hydroxy-2-propyl and R¹ is 1-hydroxyethyl;    -   R² is hydroxymethyl and R¹ is methyl;    -   R² is 1-hydroxyethyl and R¹ is methyl;    -   R² is 2-hydroxyethyl and R¹ is methyl;    -   R² is 1-hydroxy-2-propyl and R¹ is methyl;    -   R² is 2-hydroxy-2-propyl and R¹ is phenyl;    -   R² is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R¹ is 5- to 10-membered heteroaryl;    -   R² is 2-hydroxy-2-propyl and R¹ is pyridyl;    -   R² is 2-hydroxy-2-propyl and R¹ is pyrazolyl;    -   R² is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R¹ is S(O₂)CH₃;    -   R² is 2-hydroxy-2-propyl and R¹ is chloro;    -   R² is 2-hydroxy-2-propyl and R¹ is fluoro;    -   R² is C₃-C₇ cycloalkyl optionally substituted with one or more        hydroxy, and R¹ is C₁-C₆ alkyl;    -   R² is 1-hydroxy-1-cyclopropyl, and R¹ is methyl;    -   R² is 1-hydroxy-1-cyclobutyl, and R¹ is methyl;    -   R² is 1-hydroxy-1-cyclopentyl, and R¹ is methyl;    -   R² is 1-hydroxy-1-cyclohexyl, and R¹ is methyl;    -   R² is morpholinyl, and R¹ is methyl;    -   R² is 1,3-dioxolan-2-yl, and R¹ is methyl;    -   R² is 1,3-dioxolan-2-yl, and R¹ is fluoro;    -   R² is 1,3-dioxolan-2-yl, and R¹ is chloro;    -   R² is C₁-C₆ alkyl optionally substituted with one or more oxo,        and R¹ is methyl;    -   R² is (dimethylamino)methyl, and R¹ is methyl;    -   R² is COCH₃, and R¹ is methyl; or    -   R² is 2-methoxy-2-propyl, and R¹ is methyl.

In some embodiments, of the compound of formula AA,

the substituted ring A is

and R¹ and R² are one of the following combinations:

-   -   R¹ is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R² is C₁-C₆ alkyl optionally substituted with one        or more hydroxy;    -   R¹ is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R² is C₆-C₁₀ aryl;    -   R¹ is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R² is 5- to 10-membered heteroaryl;    -   R¹ is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R² is SF₅;    -   R¹ is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R² is S(O₂)C₁-C₆ alkyl;    -   R¹ is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R² is halo;    -   R¹ is C₃-C₇ cycloalkyl optionally substituted with one or more        hydroxy, and R² is C₁-C₆ alkyl;    -   R¹ is 3- to 7-membered heterocycloalkyl optionally substituted        with one or more hydroxy, and R² is C₁-C₆ alkyl;    -   R¹ is 3- to 7-membered heterocycloalkyl optionally substituted        with one or more hydroxy, and R² is halo;    -   R¹ is C₁-C₆ alkyl optionally substituted with one or more oxo,        and R² is methyl;    -   R¹ is C₁-C₆ alkyl optionally substituted with one or more C₁-C₆        alkoxy, and R² is C₁-C₆ alkyl;    -   R¹ is C₁-C₆ alkyl optionally substituted with one or more NR⁸R⁹,        and R² is C₁-C₆ alkyl;    -   R¹ is C₁-C₆ alkyl optionally substituted with one or more NR⁸R⁹,        and R² is halo;    -   R² is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R¹ is C₆-C₁₀ aryl;    -   R² is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R¹ is 5- to 10-membered heteroaryl;    -   R² is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R¹ is SF₅.    -   R² is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R¹ is S(O₂)C₁-C₆ alkyl;    -   R² is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R¹ is halo;    -   R² is C₃-C₇ cycloalkyl optionally substituted with one or more        hydroxy, and R¹ is C₁-C₆ alkyl;    -   R² is 3- to 7-membered heterocycloalkyl optionally substituted        with one or more hydroxy, and R¹ is C₁-C₆ alkyl;    -   R² is 3- to 7-membered heterocycloalkyl optionally substituted        with one or more hydroxy, and R¹ is halo;    -   R² is C₁-C₆ alkyl optionally substituted with one or more NR⁸R⁹,        and R¹ is C₁-C₆ alkyl;    -   R² is C₁-C₆ alkyl optionally substituted with one or more NR⁸R⁹,        and R¹ is halo;    -   R² is C₁-C₆ alkyl optionally substituted with one or more oxo,        and R¹ is methyl; or    -   R² is C₁-C₆ alkyl optionally substituted with one or more C₁-C₆        alkoxy, and R¹ is C₁-C₆ alkyl.

In some embodiments, of the compound of formula AA,

the substituted ring A is

and R¹ and R² are one of the following combinations:

-   -   R¹ is 1-hydroxy-2-methylpropan-2-yl, and R² is methyl;    -   R¹ is 2-hydroxy-2-propyl and R² is methyl;    -   R¹ is 2-hydroxy-2-propyl and R² is isopropyl;    -   R¹ is 2-hydroxy-2-propyl and R² is 2-hydroxy-2-propyl;    -   R¹ is 2-hydroxy-2-propyl and R² is 1-hydroxyethyl;    -   R¹ is hydroxymethyl and R² is methyl;    -   R¹ is 1-hydroxyethyl and R² is methyl;    -   R¹ is 2-hydroxyethyl and R² is methyl;    -   R¹ is 1-hydroxy-2-propyl and R² is methyl;    -   R¹ is 2-hydroxy-2-propyl and R² is phenyl;    -   R¹ is 2-hydroxy-2-propyl and R² is pyridyl;    -   R¹ is 2-hydroxy-2-propyl and R² is pyrazolyl;    -   R¹ is 2-hydroxy-2-propyl, and R² is S(O₂)CH₃;    -   R¹ is 2-hydroxy-2-propyl and R² is chloro;    -   R¹ is 2-hydroxy-2-propyl and R² is fluoro;    -   R¹ is 1-hydroxy-1-cyclopropyl, and R² is methyl;    -   R¹ is 1-hydroxy-1-cyclobutyl, and R² is methyl;    -   R¹ is 1-hydroxy-1-cyclopentyl, and R² is methyl;    -   R¹ is 1-hydroxy-1-cyclohexyl, and R² is methyl;    -   R¹ is morpholinyl, and R² is methyl;    -   R¹ is 1,3-dioxolan-2-yl, and R² is methyl;    -   R¹ is 1,3-dioxolan-2-yl, and R² is fluoro;    -   R¹ is 1,3-dioxolan-2-yl, and R² is chloro;    -   R¹ is COCH₃, and R² is methyl;    -   R¹ is 2-methoxy-2-propyl, and R² is methyl;    -   R¹ is (dimethylamino)methyl, and R² is methyl.    -   R² is 1-hydroxy-2-methylpropan-2-yl, and R¹ is methyl;    -   R² is 2-hydroxy-2-propyl and R¹ is methyl;    -   R² is 2-hydroxy-2-propyl and R¹ is isopropyl;    -   R² is 2-hydroxy-2-propyl and R¹ is 1-hydroxyethyl;    -   R² is hydroxymethyl and R¹ is methyl;    -   R² is 1-hydroxyethyl and R¹ is methyl;    -   R² is 2-hydroxyethyl and R¹ is methyl;    -   R² is 1-hydroxy-2-propyl and R¹ is methyl;    -   R² is 2-hydroxy-2-propyl and R¹ is phenyl;    -   R² is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R¹ is 5- to 10-membered heteroaryl;    -   R² is 2-hydroxy-2-propyl and R¹ is pyridyl;    -   R² is 2-hydroxy-2-propyl and R¹ is pyrazolyl;    -   R² is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R¹ is S(O₂)CH₃;    -   R² is 2-hydroxy-2-propyl and R¹ is chloro;    -   R² is 2-hydroxy-2-propyl and R¹ is fluoro;    -   R² is C₃-C₇ cycloalkyl optionally substituted with one or more        hydroxy, and R¹ is C₁-C₆ alkyl;    -   R² is 1-hydroxy-1-cyclopropyl, and R¹ is methyl;    -   R² is 1-hydroxy-1-cyclobutyl, and R¹ is methyl;    -   R² is 1-hydroxy-1-cyclopentyl, and R¹ is methyl;    -   R² is 1-hydroxy-1-cyclohexyl, and R¹ is methyl;    -   R² is morpholinyl, and R¹ is methyl;    -   R² is 1,3-dioxolan-2-yl, and R¹ is methyl;    -   R² is 1,3-dioxolan-2-yl, and R¹ is fluoro;    -   R² is 1,3-dioxolan-2-yl, and R¹ is chloro;    -   R² is C₁-C₆ alkyl optionally substituted with one or more oxo,        and R¹ is methyl;    -   R² is (dimethylamino)methyl, and R¹ is methyl;    -   R² is COCH₃, and R¹ is methyl; or    -   R² is 2-methoxy-2-propyl, and R¹ is methyl.

In some embodiments, of the compound of formula AA,

the substituted ring A is

and R¹ and R² are one of the following combinations:

-   -   R¹ is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R² is C₁-C₆ alkyl optionally substituted with one        or more hydroxy;    -   R¹ is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R² is C₆-C₁₀ aryl;    -   R¹ is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R² is 5- to 10-membered heteroaryl;    -   R¹ is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R² is SF₅;    -   R¹ is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R² is S(O₂)C₁-C₆ alkyl;    -   R¹ is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R² is halo;    -   R¹ is C₃-C₇ cycloalkyl optionally substituted with one or more        hydroxy, and R² is C₁-C₆ alkyl;    -   R¹ is 3- to 7-membered heterocycloalkyl optionally substituted        with one or more hydroxy, and R² is C₁-C₆ alkyl;    -   R¹ is 3- to 7-membered heterocycloalkyl optionally substituted        with one or more hydroxy, and R² is halo;    -   R¹ is C₁-C₆ alkyl optionally substituted with one or more oxo,        and R² is methyl;    -   R¹ is C₁-C₆ alkyl optionally substituted with one or more C₁-C₆        alkoxy, and R² is C₁-C₆ alkyl;    -   R¹ is C₁-C₆ alkyl optionally substituted with one or more NR⁸R⁹,        and R² is C₁-C₆ alkyl;    -   R¹ is C₁-C₆ alkyl optionally substituted with one or more NR⁸R⁹,        and R² is halo;    -   R² is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R¹ is C₆-C₁₀ aryl;    -   R² is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R¹ is 5- to 10-membered heteroaryl;    -   R² is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R¹ is SF₅.    -   R² is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R¹ is S(O₂)C₁-C₆ alkyl;    -   R² is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R¹ is halo;    -   R² is C₃-C₇ cycloalkyl optionally substituted with one or more        hydroxy, and R¹ is C₁-C₆ alkyl;    -   R² is 3- to 7-membered heterocycloalkyl optionally substituted        with one or more hydroxy, and R¹ is C₁-C₆ alkyl;    -   R² is 3- to 7-membered heterocycloalkyl optionally substituted        with one or more hydroxy, and R¹ is halo;    -   R² is C₁-C₆ alkyl optionally substituted with one or more NR⁸R⁹,        and R¹ is C₁-C₆ alkyl;    -   R² is C₁-C₆ alkyl optionally substituted with one or more NR⁸R⁹,        and R¹ is halo;    -   R² is C₁-C₆ alkyl optionally substituted with one or more oxo,        and R¹ is methyl; or    -   R² is C₁-C₆ alkyl optionally substituted with one or more C₁-C₆        alkoxy, and R¹ is C₁-C₆ alkyl.

In some embodiments, of the compound of formula AA,

the substituted ring A is

and R¹ and R² are one of the following combinations:

-   -   R¹ is 1-hydroxy-2-methylpropan-2-yl, and R² is methyl;    -   R¹ is 2-hydroxy-2-propyl and R² is methyl;    -   R¹ is 2-hydroxy-2-propyl and R² is isopropyl;    -   R¹ is 2-hydroxy-2-propyl and R² is 2-hydroxy-2-propyl;    -   R¹ is 2-hydroxy-2-propyl and R² is 1-hydroxyethyl;    -   R¹ is hydroxymethyl and R² is methyl;    -   R¹ is 1-hydroxyethyl and R² is methyl;    -   R¹ is 2-hydroxyethyl and R² is methyl;    -   R¹ is 1-hydroxy-2-propyl and R² is methyl;    -   R¹ is 2-hydroxy-2-propyl and R² is phenyl;    -   R¹ is 2-hydroxy-2-propyl and R² is pyridyl;    -   R¹ is 2-hydroxy-2-propyl and R² is pyrazolyl;    -   R¹ is 2-hydroxy-2-propyl, and R² is S(O₂)CH₃;    -   R¹ is 2-hydroxy-2-propyl and R² is chloro;    -   R¹ is 2-hydroxy-2-propyl and R² is fluoro;    -   R¹ is 1-hydroxy-1-cyclopropyl, and R² is methyl;    -   R¹ is 1-hydroxy-1-cyclobutyl, and R² is methyl;    -   R¹ is 1-hydroxy-1-cyclopentyl, and R² is methyl;    -   R¹ is 1-hydroxy-1-cyclohexyl, and R² is methyl;    -   R¹ is morpholinyl, and R² is methyl;    -   R¹ is 1,3-dioxolan-2-yl, and R² is methyl;    -   R¹ is 1,3-dioxolan-2-yl, and R² is fluoro;    -   R¹ is 1,3-dioxolan-2-yl, and R² is chloro;    -   R¹ is COCH₃, and R² is methyl;    -   R¹ is 2-methoxy-2-propyl, and R² is methyl;    -   R¹ is (dimethylamino)methyl, and R² is methyl.    -   R² is 1-hydroxy-2-methylpropan-2-yl, and R¹ is methyl;    -   R² is 2-hydroxy-2-propyl and R¹ is methyl;    -   R² is 2-hydroxy-2-propyl and R¹ is isopropyl;    -   R² is 2-hydroxy-2-propyl and R¹ is 1-hydroxyethyl;    -   R² is hydroxymethyl and R¹ is methyl;    -   R² is 1-hydroxyethyl and R¹ is methyl;    -   R² is 2-hydroxyethyl and R¹ is methyl;    -   R² is 1-hydroxy-2-propyl and R¹ is methyl;    -   R² is 2-hydroxy-2-propyl and R¹ is phenyl;    -   R² is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R¹ is 5- to 10-membered heteroaryl;    -   R² is 2-hydroxy-2-propyl and R¹ is pyridyl;    -   R² is 2-hydroxy-2-propyl and R¹ is pyrazolyl;    -   R² is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R¹ is S(O₂)CH₃;    -   R² is 2-hydroxy-2-propyl and R¹ is chloro;    -   R² is 2-hydroxy-2-propyl and R¹ is fluoro;    -   R² is C₃-C₇ cycloalkyl optionally substituted with one or more        hydroxy, and R¹ is C₁-C₆ alkyl;    -   R² is 1-hydroxy-1-cyclopropyl, and R¹ is methyl;    -   R² is 1-hydroxy-1-cyclobutyl, and R¹ is methyl;    -   R² is 1-hydroxy-1-cyclopentyl, and R¹ is methyl;    -   R² is 1-hydroxy-1-cyclohexyl, and R¹ is methyl;    -   R² is morpholinyl, and R¹ is methyl;    -   R² is 1,3-dioxolan-2-yl, and R¹ is methyl;    -   R² is 1,3-dioxolan-2-yl, and R¹ is fluoro;    -   R² is 1,3-dioxolan-2-yl, and R¹ is chloro;    -   R² is C₁-C₆ alkyl optionally substituted with one or more oxo,        and R¹ is methyl;    -   R² is (dimethylamino)methyl, and R¹ is methyl;    -   R² is COCH₃, and R¹ is methyl; or    -   R² is 2-methoxy-2-propyl, and R¹ is methyl.

In some embodiments, of the compound of formula AA,

the substituted ring A is

and R¹ and R² are one of the following combinations:

-   -   R¹ is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R² is C₁-C₆ alkyl optionally substituted with one        or more hydroxy;    -   R¹ is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R² is C₆-C₁₀ aryl;    -   R¹ is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R² is 5- to 10-membered heteroaryl;    -   R¹ is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R² is SF₅;    -   R¹ is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R² is S(O₂)C₁-C₆ alkyl;    -   R¹ is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R² is halo;    -   R¹ is C₃-C₇ cycloalkyl optionally substituted with one or more        hydroxy, and R² is C₁-C₆ alkyl;    -   R¹ is 3- to 7-membered heterocycloalkyl optionally substituted        with one or more hydroxy, and R² is C₁-C₆ alkyl;    -   R¹ is 3- to 7-membered heterocycloalkyl optionally substituted        with one or more hydroxy, and R² is halo;    -   R¹ is C₁-C₆ alkyl optionally substituted with one or more oxo,        and R² is methyl;    -   R¹ is C₁-C₆ alkyl optionally substituted with one or more C₁-C₆        alkoxy, and R² is C₁-C₆ alkyl;    -   R¹ is C₁-C₆ alkyl optionally substituted with one or more NR⁸R⁹,        and R² is C₁-C₆ alkyl;    -   R¹ is C₁-C₆ alkyl optionally substituted with one or more NR⁸R⁹,        and R² is halo;    -   R² is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R¹ is C₆-C₁₀ aryl;    -   R² is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R¹ is 5- to 10-membered heteroaryl;    -   R² is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R¹ is SF₅.    -   R² is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R¹ is S(O₂)C₁-C₆ alkyl;    -   R² is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R¹ is halo;    -   R² is C₃-C₇ cycloalkyl optionally substituted with one or more        hydroxy, and R¹ is C₁-C₆ alkyl;    -   R² is 3- to 7-membered heterocycloalkyl optionally substituted        with one or more hydroxy, and R¹ is C₁-C₆ alkyl;    -   R² is 3- to 7-membered heterocycloalkyl optionally substituted        with one or more hydroxy, and R¹ is halo;    -   R² is C₁-C₆ alkyl optionally substituted with one or more NR⁸R⁹,        and R¹ is C₁-C₆ alkyl;    -   R² is C₁-C₆ alkyl optionally substituted with one or more NR⁸R⁹,        and R¹ is halo;    -   R² is C₁-C₆ alkyl optionally substituted with one or more oxo,        and R¹ is methyl; or    -   R² is C₁-C₆ alkyl optionally substituted with one or more C₁-C₆        alkoxy, and R¹ is C₁-C₆ alkyl.

In some embodiments, of the compound of formula AA,

the substituted ring A is

and R¹ and R² are one of the following combinations:

-   -   R¹ is 1-hydroxy-2-methylpropan-2-yl, and R² is methyl;    -   R¹ is 2-hydroxy-2-propyl and R² is methyl;    -   R¹ is 2-hydroxy-2-propyl and R² is isopropyl;    -   R¹ is 2-hydroxy-2-propyl and R² is 2-hydroxy-2-propyl;    -   R¹ is 2-hydroxy-2-propyl and R² is 1-hydroxyethyl;    -   R¹ is hydroxymethyl and R² is methyl;    -   R¹ is 1-hydroxyethyl and R² is methyl;    -   R¹ is 2-hydroxyethyl and R² is methyl;    -   R¹ is 1-hydroxy-2-propyl and R² is methyl;    -   R¹ is 2-hydroxy-2-propyl and R² is phenyl;    -   R¹ is 2-hydroxy-2-propyl and R² is pyridyl;    -   R¹ is 2-hydroxy-2-propyl and R² is pyrazolyl;    -   R¹ is 2-hydroxy-2-propyl, and R² is S(O₂)CH₃;    -   R¹ is 2-hydroxy-2-propyl and R² is chloro;    -   R¹ is 2-hydroxy-2-propyl and R² is fluoro;    -   R¹ is 1-hydroxy-1-cyclopropyl, and R² is methyl;    -   R¹ is 1-hydroxy-1-cyclobutyl, and R² is methyl;    -   R¹ is 1-hydroxy-1-cyclopentyl, and R² is methyl;    -   R¹ is 1-hydroxy-1-cyclohexyl, and R² is methyl;    -   R¹ is morpholinyl, and R² is methyl;    -   R¹ is 1,3-dioxolan-2-yl, and R² is methyl;    -   R¹ is 1,3-dioxolan-2-yl, and R² is fluoro;    -   R¹ is 1,3-dioxolan-2-yl, and R² is chloro;    -   R¹ is COCH₃, and R² is methyl;    -   R¹ is 2-methoxy-2-propyl, and R² is methyl;    -   R¹ is (dimethylamino)methyl, and R² is methyl.    -   R² is 1-hydroxy-2-methylpropan-2-yl, and R¹ is methyl;    -   R² is 2-hydroxy-2-propyl and R¹ is methyl;    -   R² is 2-hydroxy-2-propyl and R¹ is isopropyl;    -   R² is 2-hydroxy-2-propyl and R¹ is 1-hydroxyethyl;    -   R² is hydroxymethyl and R¹ is methyl;    -   R² is 1-hydroxyethyl and R¹ is methyl;    -   R² is 2-hydroxyethyl and R¹ is methyl;    -   R² is 1-hydroxy-2-propyl and R¹ is methyl;    -   R² is 2-hydroxy-2-propyl and R¹ is phenyl;    -   R² is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R¹ is 5- to 10-membered heteroaryl;    -   R² is 2-hydroxy-2-propyl and R¹ is pyridyl;    -   R² is 2-hydroxy-2-propyl and R¹ is pyrazolyl;    -   R² is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R¹ is S(O₂)CH₃;    -   R² is 2-hydroxy-2-propyl and R¹ is chloro;    -   R² is 2-hydroxy-2-propyl and R¹ is fluoro;    -   R² is C₃-C₇ cycloalkyl optionally substituted with one or more        hydroxy, and R¹ is C₁-C₆ alkyl;    -   R² is 1-hydroxy-1-cyclopropyl, and R¹ is methyl;    -   R² is 1-hydroxy-1-cyclobutyl, and R¹ is methyl;    -   R² is 1-hydroxy-1-cyclopentyl, and R¹ is methyl;    -   R² is 1-hydroxy-1-cyclohexyl, and R¹ is methyl;    -   R² is morpholinyl, and R¹ is methyl;    -   R² is 1,3-dioxolan-2-yl, and R¹ is methyl;    -   R² is 1,3-dioxolan-2-yl, and R¹ is fluoro;    -   R² is 1,3-dioxolan-2-yl, and R¹ is chloro;    -   R² is C₁-C₆ alkyl optionally substituted with one or more oxo,        and R¹ is methyl;    -   R² is (dimethylamino)methyl, and R¹ is methyl;    -   R² is COCH₃, and R¹ is methyl; or    -   R² is 2-methoxy-2-propyl, and R¹ is methyl.

In some embodiments, of the compound of formula AA,

the substituted ring A is

and R¹ and R² are one of the following combinations:

-   -   R¹ is 1-hydroxy-2-methylpropan-2-yl, and R² is methyl;    -   R¹ is 2-hydroxy-2-propyl and R² is methyl;    -   R¹ is 2-hydroxy-2-propyl and R² is isopropyl;    -   R¹ is 2-hydroxy-2-propyl and R² is 2-hydroxy-2-propyl;    -   R¹ is 2-hydroxy-2-propyl and R² is 1-hydroxyethyl;    -   R¹ is hydroxymethyl and R² is methyl;    -   R¹ is 1-hydroxyethyl and R² is methyl;    -   R¹ is 2-hydroxyethyl and R² is methyl;    -   R¹ is 1-hydroxy-2-propyl and R² is methyl;    -   R¹ is 2-hydroxy-2-propyl and R² is phenyl;    -   R¹ is 2-hydroxy-2-propyl and R² is pyridyl;    -   R¹ is 2-hydroxy-2-propyl and R² is pyrazolyl;    -   R¹ is 2-hydroxy-2-propyl, and R² is S(O₂)CH₃;    -   R¹ is 2-hydroxy-2-propyl and R² is chloro;    -   R¹ is 2-hydroxy-2-propyl and R² is fluoro;    -   R¹ is 1-hydroxy-1-cyclopropyl, and R² is methyl;    -   R¹ is 1-hydroxy-1-cyclobutyl, and R² is methyl;    -   R¹ is 1-hydroxy-1-cyclopentyl, and R² is methyl;    -   R¹ is 1-hydroxy-1-cyclohexyl, and R² is methyl;    -   R¹ is morpholinyl, and R² is methyl;    -   R¹ is 1,3-dioxolan-2-yl, and R² is methyl;    -   R¹ is 1,3-dioxolan-2-yl, and R² is fluoro;    -   R¹ is 1,3-dioxolan-2-yl, and R² is chloro;    -   R¹ is COCH₃, and R² is methyl;    -   R¹ is 2-methoxy-2-propyl, and R² is methyl;    -   R¹ is (dimethylamino)methyl, and R² is methyl.    -   R² is 1-hydroxy-2-methylpropan-2-yl, and R¹ is methyl;    -   R² is 2-hydroxy-2-propyl and R¹ is methyl;    -   R² is 2-hydroxy-2-propyl and R¹ is isopropyl;    -   R² is 2-hydroxy-2-propyl and R¹ is 1-hydroxyethyl;    -   R² is hydroxymethyl and R¹ is methyl;    -   R² is 1-hydroxyethyl and R¹ is methyl;    -   R² is 2-hydroxyethyl and R¹ is methyl;    -   R² is 1-hydroxy-2-propyl and R¹ is methyl;    -   R² is 2-hydroxy-2-propyl and R¹ is phenyl;    -   R² is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R¹ is 5- to 10-membered heteroaryl;    -   R² is 2-hydroxy-2-propyl and R¹ is pyridyl;    -   R² is 2-hydroxy-2-propyl and R¹ is pyrazolyl;    -   R² is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R¹ is S(O₂)CH₃;    -   R² is 2-hydroxy-2-propyl and R¹ is chloro;    -   R² is 2-hydroxy-2-propyl and R¹ is fluoro;    -   R² is C₃-C₇ cycloalkyl optionally substituted with one or more        hydroxy, and R¹ is C₁-C₆ alkyl;    -   R² is 1-hydroxy-1-cyclopropyl, and R¹ is methyl;    -   R² is 1-hydroxy-1-cyclobutyl, and R¹ is methyl;    -   R² is 1-hydroxy-1-cyclopentyl, and R¹ is methyl;    -   R² is 1-hydroxy-1-cyclohexyl, and R¹ is methyl;    -   R² is morpholinyl, and R¹ is methyl;    -   R² is 1,3-dioxolan-2-yl, and R¹ is methyl;    -   R² is 1,3-dioxolan-2-yl, and R¹ is fluoro;    -   R² is 1,3-dioxolan-2-yl, and R¹ is chloro;    -   R² is C₁-C₆ alkyl optionally substituted with one or more oxo,        and R¹ is methyl;    -   R² is (dimethylamino)methyl, and R¹ is methyl;    -   R² is COCH₃, and R¹ is methyl; or    -   R² is 2-methoxy-2-propyl, and R¹ is methyl.

In some embodiments, of the compound of formula AA,

the substituted ring A is

and R¹ and R² are one of the following combinations:

-   -   R¹ is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R² is C₁-C₆ alkyl optionally substituted with one        or more hydroxy;    -   R¹ is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R² is C₆-C₁₀ aryl;    -   R¹ is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R² is 5- to 10-membered heteroaryl;    -   R¹ is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R² is SF₅;    -   R¹ is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R² is S(O₂)C₁-C₆ alkyl;    -   R¹ is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R² is halo;    -   R¹ is C₃-C₇ cycloalkyl optionally substituted with one or more        hydroxy, and R² is C₁-C₆ alkyl;    -   R¹ is 3- to 7-membered heterocycloalkyl optionally substituted        with one or more hydroxy, and R² is C₁-C₆ alkyl;    -   R¹ is 3- to 7-membered heterocycloalkyl optionally substituted        with one or more hydroxy, and R² is halo;    -   R¹ is C₁-C₆ alkyl optionally substituted with one or more oxo,        and R² is methyl;    -   R¹ is C₁-C₆ alkyl optionally substituted with one or more C₁-C₆        alkoxy, and R² is C₁-C₆ alkyl;    -   R¹ is C₁-C₆ alkyl optionally substituted with one or more NR⁸R⁹,        and R² is C₁-C₆ alkyl;    -   R¹ is C₁-C₆ alkyl optionally substituted with one or more NR⁸R⁹,        and R² is halo;    -   R² is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R¹ is C₆-C₁₀ aryl;    -   R² is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R¹ is 5- to 10-membered heteroaryl;    -   R² is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R¹ is SF₅.    -   R² is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R¹ is S(O₂)C₁-C₆ alkyl;    -   R² is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R¹ is halo;    -   R² is C₃-C₇ cycloalkyl optionally substituted with one or more        hydroxy, and R¹ is C₁-C₆ alkyl;    -   R² is 3- to 7-membered heterocycloalkyl optionally substituted        with one or more hydroxy, and R¹ is C₁-C₆ alkyl;    -   R² is 3- to 7-membered heterocycloalkyl optionally substituted        with one or more hydroxy, and R¹ is halo;    -   R² is C₁-C₆ alkyl optionally substituted with one or more NR⁸R⁹,        and R¹ is C₁-C₆ alkyl;    -   R² is C₁-C₆ alkyl optionally substituted with one or more NR⁸R⁹,        and R¹ is halo;    -   R² is C₁-C₆ alkyl optionally substituted with one or more oxo,        and R¹ is methyl; or    -   R² is C₁-C₆ alkyl optionally substituted with one or more C₁-C₆        alkoxy, and R¹ is C₁-C₆ alkyl.

In some embodiments, of the compound of formula AA,

the substituted ring A is

and R¹ and R² are one of the following combinations:

-   -   R¹ is 1-hydroxy-2-methylpropan-2-yl, and R² is methyl;    -   R¹ is 2-hydroxy-2-propyl and R² is methyl;    -   R¹ is 2-hydroxy-2-propyl and R² is isopropyl;    -   R¹ is 2-hydroxy-2-propyl and R² is 2-hydroxy-2-propyl;    -   R¹ is 2-hydroxy-2-propyl and R² is 1-hydroxyethyl;    -   R¹ is hydroxymethyl and R² is methyl;    -   R¹ is 1-hydroxyethyl and R² is methyl;    -   R¹ is 2-hydroxyethyl and R² is methyl;    -   R¹ is 1-hydroxy-2-propyl and R² is methyl;    -   R¹ is 2-hydroxy-2-propyl and R² is phenyl;    -   R¹ is 2-hydroxy-2-propyl and R² is pyridyl;    -   R¹ is 2-hydroxy-2-propyl and R² is pyrazolyl;    -   R¹ is 2-hydroxy-2-propyl, and R² is S(O₂)CH₃;    -   R¹ is 2-hydroxy-2-propyl and R² is chloro;    -   R¹ is 2-hydroxy-2-propyl and R² is fluoro;    -   R¹ is 1-hydroxy-1-cyclopropyl, and R² is methyl;    -   R¹ is 1-hydroxy-1-cyclobutyl, and R² is methyl;    -   R¹ is 1-hydroxy-1-cyclopentyl, and R² is methyl;    -   R¹ is 1-hydroxy-1-cyclohexyl, and R² is methyl;    -   R¹ is morpholinyl, and R² is methyl;    -   R¹ is 1,3-dioxolan-2-yl, and R² is methyl;    -   R¹ is 1,3-dioxolan-2-yl, and R² is fluoro;    -   R¹ is 1,3-dioxolan-2-yl, and R² is chloro;    -   R¹ is COCH₃, and R² is methyl;    -   R¹ is 2-methoxy-2-propyl, and R² is methyl;    -   R¹ is (dimethylamino)methyl, and R² is methyl.    -   R² is 1-hydroxy-2-methylpropan-2-yl, and R¹ is methyl;    -   R² is 2-hydroxy-2-propyl and R¹ is methyl;    -   R² is 2-hydroxy-2-propyl and R¹ is isopropyl;    -   R² is 2-hydroxy-2-propyl and R¹ is 1-hydroxyethyl;    -   R² is hydroxymethyl and R¹ is methyl;    -   R² is 1-hydroxyethyl and R¹ is methyl;    -   R² is 2-hydroxyethyl and R¹ is methyl;    -   R² is 1-hydroxy-2-propyl and R¹ is methyl;    -   R² is 2-hydroxy-2-propyl and R¹ is phenyl;    -   R² is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R¹ is 5- to 10-membered heteroaryl;    -   R² is 2-hydroxy-2-propyl and R¹ is pyridyl;    -   R² is 2-hydroxy-2-propyl and R¹ is pyrazolyl;    -   R² is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R¹ is S(O₂)CH₃;    -   R² is 2-hydroxy-2-propyl and R¹ is chloro;    -   R² is 2-hydroxy-2-propyl and R¹ is fluoro;    -   R² is C₃-C₇ cycloalkyl optionally substituted with one or more        hydroxy, and R¹ is C₁-C₆ alkyl;    -   R² is 1-hydroxy-1-cyclopropyl, and R¹ is methyl;    -   R² is 1-hydroxy-1-cyclobutyl, and R¹ is methyl;    -   R² is 1-hydroxy-1-cyclopentyl, and R¹ is methyl;    -   R² is 1-hydroxy-1-cyclohexyl, and R¹ is methyl;    -   R² is morpholinyl, and R¹ is methyl;    -   R² is 1,3-dioxolan-2-yl, and R¹ is methyl;    -   R² is 1,3-dioxolan-2-yl, and R¹ is fluoro;    -   R² is 1,3-dioxolan-2-yl, and R¹ is chloro;    -   R² is C₁-C₆ alkyl optionally substituted with one or more oxo,        and R¹ is methyl;    -   R² is (dimethylamino)methyl, and R¹ is methyl;    -   R² is COCH₃, and R¹ is methyl; or    -   R² is 2-methoxy-2-propyl, and R¹ is methyl.

In some embodiments, of the compound of formula AA,

the substituted ring A is

and R¹ and R² are one of the following combinations:

-   -   R¹ is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R² is C₁-C₆ alkyl optionally substituted with one        or more hydroxy;    -   R¹ is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R² is C₆-C₁₀ aryl;    -   R¹ is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R² is 5- to 10-membered heteroaryl;    -   R¹ is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R² is SF₅;    -   R¹ is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R² is S(O₂)C₁-C₆ alkyl;    -   R¹ is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R² is halo;    -   R¹ is C₃-C₇ cycloalkyl optionally substituted with one or more        hydroxy, and R² is C₁-C₆ alkyl;    -   R¹ is 3- to 7-membered heterocycloalkyl optionally substituted        with one or more hydroxy, and R² is C₁-C₆ alkyl;    -   R¹ is 3- to 7-membered heterocycloalkyl optionally substituted        with one or more hydroxy, and R² is halo;    -   R¹ is C₁-C₆ alkyl optionally substituted with one or more oxo,        and R² is methyl;    -   R¹ is C₁-C₆ alkyl optionally substituted with one or more C₁-C₆        alkoxy, and R² is C₁-C₆ alkyl;    -   R¹ is C₁-C₆ alkyl optionally substituted with one or more NR⁸R⁹,        and R² is C₁-C₆ alkyl;    -   R¹ is C₁-C₆ alkyl optionally substituted with one or more NR⁸R⁹,        and R² is halo;    -   R² is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R¹ is C₆-C₁₀ aryl;    -   R² is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R¹ is 5- to 10-membered heteroaryl;    -   R² is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R¹ is SF₅. R² is C₁-C₆ alkyl optionally substituted        with one or more hydroxy, and R¹ is S(O₂)C₁-C₆ alkyl;    -   R² is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R¹ is halo;    -   R² is C₃-C₇ cycloalkyl optionally substituted with one or more        hydroxy, and R¹ is C₁-C₆ alkyl;    -   R² is 3- to 7-membered heterocycloalkyl optionally substituted        with one or more hydroxy, and R¹ is C₁-C₆ alkyl;    -   R² is 3- to 7-membered heterocycloalkyl optionally substituted        with one or more hydroxy, and R¹ is halo;    -   R² is C₁-C₆ alkyl optionally substituted with one or more NR⁸R⁹,        and R¹ is C₁-C₆ alkyl;    -   R² is C₁-C₆ alkyl optionally substituted with one or more NR⁸R⁹,        and R¹ is halo;    -   R² is C₁-C₆ alkyl optionally substituted with one or more oxo,        and R¹ is methyl; or    -   R² is C₁-C₆ alkyl optionally substituted with one or more C₁-C₆        alkoxy, and R¹ is C₁-C₆ alkyl.

In some embodiments, of the compound of formula AA,

the substituted ring A is

and R¹ and R² are one of the following combinations:

-   -   R¹ is 1-hydroxy-2-methylpropan-2-yl, and R² is methyl;    -   R¹ is 2-hydroxy-2-propyl and R² is methyl;    -   R¹ is 2-hydroxy-2-propyl and R² is isopropyl;    -   R¹ is 2-hydroxy-2-propyl and R² is 2-hydroxy-2-propyl;    -   R¹ is 2-hydroxy-2-propyl and R² is 1-hydroxyethyl;    -   R¹ is hydroxymethyl and R² is methyl;    -   R¹ is 1-hydroxyethyl and R² is methyl;    -   R¹ is 2-hydroxyethyl and R² is methyl;    -   R¹ is 1-hydroxy-2-propyl and R² is methyl;    -   R¹ is 2-hydroxy-2-propyl and R² is phenyl;    -   R¹ is 2-hydroxy-2-propyl and R² is pyridyl;    -   R¹ is 2-hydroxy-2-propyl and R² is pyrazolyl;    -   R¹ is 2-hydroxy-2-propyl, and R² is S(O₂)CH₃;    -   R¹ is 2-hydroxy-2-propyl and R² is chloro;    -   R¹ is 2-hydroxy-2-propyl and R² is fluoro;    -   R¹ is 1-hydroxy-1-cyclopropyl, and R² is methyl;    -   R¹ is 1-hydroxy-1-cyclobutyl, and R² is methyl;    -   R¹ is 1-hydroxy-1-cyclopentyl, and R² is methyl;    -   R¹ is 1-hydroxy-1-cyclohexyl, and R² is methyl;    -   R¹ is morpholinyl, and R² is methyl;    -   R¹ is 1,3-dioxolan-2-yl, and R² is methyl;    -   R¹ is 1,3-dioxolan-2-yl, and R² is fluoro;    -   R¹ is 1,3-dioxolan-2-yl, and R² is chloro;    -   R¹ is COCH₃, and R² is methyl;    -   R¹ is 2-methoxy-2-propyl, and R² is methyl;    -   R¹ is (dimethylamino)methyl, and R² is methyl.    -   R² is 1-hydroxy-2-methylpropan-2-yl, and R¹ is methyl;    -   R² is 2-hydroxy-2-propyl and R¹ is methyl;    -   R² is 2-hydroxy-2-propyl and R¹ is isopropyl;    -   R² is 2-hydroxy-2-propyl and R¹ is 1-hydroxyethyl;    -   R² is hydroxymethyl and R¹ is methyl;    -   R² is 1-hydroxyethyl and R¹ is methyl;    -   R² is 2-hydroxyethyl and R¹ is methyl;    -   R² is 1-hydroxy-2-propyl and R¹ is methyl;    -   R² is 2-hydroxy-2-propyl and R¹ is phenyl;    -   R² is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R¹ is 5- to 10-membered heteroaryl;    -   R² is 2-hydroxy-2-propyl and R¹ is pyridyl;    -   R² is 2-hydroxy-2-propyl and R¹ is pyrazolyl;    -   R² is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R¹ is S(O₂)CH₃;    -   R² is 2-hydroxy-2-propyl and R¹ is chloro;    -   R² is 2-hydroxy-2-propyl and R¹ is fluoro;    -   R² is C₃-C₇ cycloalkyl optionally substituted with one or more        hydroxy, and R¹ is C₁-C₆ alkyl;    -   R² is 1-hydroxy-1-cyclopropyl, and R¹ is methyl;    -   R² is 1-hydroxy-1-cyclobutyl, and R¹ is methyl;    -   R² is 1-hydroxy-1-cyclopentyl, and R¹ is methyl;    -   R² is 1-hydroxy-1-cyclohexyl, and R¹ is methyl;    -   R² is morpholinyl, and R¹ is methyl;    -   R² is 1,3-dioxolan-2-yl, and R¹ is methyl;    -   R² is 1,3-dioxolan-2-yl, and R¹ is fluoro;    -   R² is 1,3-dioxolan-2-yl, and R¹ is chloro;    -   R² is C₁-C₆ alkyl optionally substituted with one or more oxo,        and R¹ is methyl;    -   R² is (dimethylamino)methyl, and R¹ is methyl;    -   R² is COCH₃, and R¹ is methyl; or    -   R² is 2-methoxy-2-propyl, and R¹ is methyl.

In some embodiments, of the compound of formula AA,

the substituted ring A is

and R¹ and R² are one of the following combinations:

-   -   R¹ is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R² is C₁-C₆ alkyl optionally substituted with one        or more hydroxy;    -   R¹ is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R² is C₆-C₁₀ aryl;    -   R¹ is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R² is 5- to 10-membered heteroaryl;    -   R¹ is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R² is SF₅;    -   R¹ is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R² is S(O₂)C₁-C₆ alkyl;    -   R¹ is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R² is halo;    -   R¹ is C₃-C₇ cycloalkyl optionally substituted with one or more        hydroxy, and R² is C₁-C₆ alkyl;    -   R¹ is 3- to 7-membered heterocycloalkyl optionally substituted        with one or more hydroxy, and R² is C₁-C₆ alkyl;    -   R¹ is 3- to 7-membered heterocycloalkyl optionally substituted        with one or more hydroxy, and R² is halo;    -   R¹ is C₁-C₆ alkyl optionally substituted with one or more oxo,        and R² is methyl;    -   R¹ is C₁-C₆ alkyl optionally substituted with one or more C₁-C₆        alkoxy, and R² is C₁-C₆ alkyl;    -   R¹ is C₁-C₆ alkyl optionally substituted with one or more NR⁸R⁹,        and R² is C₁-C₆ alkyl;    -   R¹ is C₁-C₆ alkyl optionally substituted with one or more NR⁸R⁹,        and R² is halo;    -   R² is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R¹ is C₆-C₁₀ aryl;    -   R² is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R¹ is 5- to 10-membered heteroaryl;    -   R² is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R¹ is SF₅.    -   R² is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R¹ is S(O₂)C₁-C₆ alkyl;    -   R² is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R¹ is halo;    -   R² is C₃-C₇ cycloalkyl optionally substituted with one or more        hydroxy, and R¹ is C₁-C₆ alkyl;    -   R² is 3- to 7-membered heterocycloalkyl optionally substituted        with one or more hydroxy, and R¹ is C₁-C₆ alkyl;    -   R² is 3- to 7-membered heterocycloalkyl optionally substituted        with one or more hydroxy, and R¹ is halo;    -   R² is C₁-C₆ alkyl optionally substituted with one or more NR⁸R⁹,        and R¹ is C₁-C₆ alkyl;    -   R² is C₁-C₆ alkyl optionally substituted with one or more NR⁸R⁹,        and R¹ is halo;    -   R² is C₁-C₆ alkyl optionally substituted with one or more oxo,        and R¹ is methyl; or    -   R² is C₁-C₆ alkyl optionally substituted with one or more C₁-C₆        alkoxy, and R¹ is C₁-C₆ alkyl.

In some embodiments, of the compound of formula AA,

the substituted ring A is

and R¹ and R² are one of the following combinations:

-   -   R¹ is 1-hydroxy-2-methylpropan-2-yl, and R² is methyl;    -   R¹ is 2-hydroxy-2-propyl and R² is methyl;    -   R¹ is 2-hydroxy-2-propyl and R² is isopropyl;    -   R¹ is 2-hydroxy-2-propyl and R² is 2-hydroxy-2-propyl;    -   R¹ is 2-hydroxy-2-propyl and R² is 1-hydroxyethyl;    -   R¹ is hydroxymethyl and R² is methyl;    -   R¹ is 1-hydroxyethyl and R² is methyl;    -   R¹ is 2-hydroxyethyl and R² is methyl;    -   R¹ is 1-hydroxy-2-propyl and R² is methyl;    -   R¹ is 2-hydroxy-2-propyl and R² is phenyl;    -   R¹ is 2-hydroxy-2-propyl and R² is pyridyl;    -   R¹ is 2-hydroxy-2-propyl and R² is pyrazolyl;    -   R¹ is 2-hydroxy-2-propyl, and R² is S(O₂)CH₃;    -   R¹ is 2-hydroxy-2-propyl and R² is chloro;    -   R¹ is 2-hydroxy-2-propyl and R² is fluoro;    -   R¹ is 1-hydroxy-1-cyclopropyl, and R² is methyl;    -   R¹ is 1-hydroxy-1-cyclobutyl, and R² is methyl;    -   R¹ is 1-hydroxy-1-cyclopentyl, and R² is methyl;    -   R¹ is 1-hydroxy-1-cyclohexyl, and R² is methyl;    -   R¹ is morpholinyl, and R² is methyl;    -   R¹ is 1,3-dioxolan-2-yl, and R² is methyl;    -   R¹ is 1,3-dioxolan-2-yl, and R² is fluoro;    -   R¹ is 1,3-dioxolan-2-yl, and R² is chloro;    -   R¹ is COCH₃, and R² is methyl;    -   R¹ is 2-methoxy-2-propyl, and R² is methyl;    -   R¹ is (dimethylamino)methyl, and R² is methyl.    -   R² is 1-hydroxy-2-methylpropan-2-yl, and R¹ is methyl;    -   R² is 2-hydroxy-2-propyl and R¹ is methyl;    -   R² is 2-hydroxy-2-propyl and R¹ is isopropyl;    -   R² is 2-hydroxy-2-propyl and R¹ is 1-hydroxyethyl;    -   R² is hydroxymethyl and R¹ is methyl;    -   R² is 1-hydroxyethyl and R¹ is methyl;    -   R² is 2-hydroxyethyl and R¹ is methyl;    -   R² is 1-hydroxy-2-propyl and R¹ is methyl;    -   R² is 2-hydroxy-2-propyl and R¹ is phenyl;    -   R² is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R¹ is 5- to 10-membered heteroaryl;    -   R² is 2-hydroxy-2-propyl and R¹ is pyridyl;    -   R² is 2-hydroxy-2-propyl and R¹ is pyrazolyl;    -   R² is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R¹ is S(O₂)CH₃;    -   R² is 2-hydroxy-2-propyl and R¹ is chloro;    -   R² is 2-hydroxy-2-propyl and R¹ is fluoro;    -   R² is C₃-C₇ cycloalkyl optionally substituted with one or more        hydroxy, and R¹ is C₁-C₆ alkyl;    -   R² is 1-hydroxy-1-cyclopropyl, and R¹ is methyl;    -   R² is 1-hydroxy-1-cyclobutyl, and R¹ is methyl;    -   R² is 1-hydroxy-1-cyclopentyl, and R¹ is methyl;    -   R² is 1-hydroxy-1-cyclohexyl, and R¹ is methyl;    -   R² is morpholinyl, and R¹ is methyl;    -   R² is 1,3-dioxolan-2-yl, and R¹ is methyl;    -   R² is 1,3-dioxolan-2-yl, and R¹ is fluoro;    -   R² is 1,3-dioxolan-2-yl, and R¹ is chloro;    -   R² is C₁-C₆ alkyl optionally substituted with one or more oxo,        and R¹ is methyl;    -   R² is (dimethylamino)methyl, and R¹ is methyl;    -   R² is COCH₃, and R¹ is methyl; or    -   R² is 2-methoxy-2-propyl, and R¹ is methyl.

In some embodiments, of the compound of formula AA,

the substituted ring A is

and R¹ and R² are one of the following combinations:

-   -   R¹ is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R² is C₁-C₆ alkyl optionally substituted with one        or more hydroxy;    -   R¹ is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R² is C₆-C₁₀ aryl;    -   R¹ is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R² is 5- to 10-membered heteroaryl;    -   R¹ is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R² is SF₅;    -   R¹ is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R² is S(O₂)C₁-C₆ alkyl;    -   R¹ is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R² is halo;    -   R¹ is C₃-C₇ cycloalkyl optionally substituted with one or more        hydroxy, and R² is C₁-C₆ alkyl;    -   R¹ is 3- to 7-membered heterocycloalkyl optionally substituted        with one or more hydroxy, and R² is C₁-C₆ alkyl;    -   R¹ is 3- to 7-membered heterocycloalkyl optionally substituted        with one or more hydroxy, and R² is halo;    -   R¹ is C₁-C₆ alkyl optionally substituted with one or more oxo,        and R² is methyl;    -   R¹ is C₁-C₆ alkyl optionally substituted with one or more C₁-C₆        alkoxy, and R² is C₁-C₆ alkyl;    -   R¹ is C₁-C₆ alkyl optionally substituted with one or more NR⁸R⁹,        and R² is C₁-C₆ alkyl;    -   R¹ is C₁-C₆ alkyl optionally substituted with one or more NR⁸R⁹,        and R² is halo;    -   R² is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R¹ is C₆-C₁₀ aryl;    -   R² is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R¹ is 5- to 10-membered heteroaryl;    -   R² is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R¹ is SF₅.    -   R² is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R¹ is S(O₂)C₁-C₆ alkyl;    -   R² is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R¹ is halo;    -   R² is C₃-C₇ cycloalkyl optionally substituted with one or more        hydroxy, and R¹ is C₁-C₆ alkyl;    -   R² is 3- to 7-membered heterocycloalkyl optionally substituted        with one or more hydroxy, and R¹ is C₁-C₆ alkyl;    -   R² is 3- to 7-membered heterocycloalkyl optionally substituted        with one or more hydroxy, and R¹ is halo;    -   R² is C₁-C₆ alkyl optionally substituted with one or more NR⁸R⁹,        and R¹ is C₁-C₆ alkyl;    -   R² is C₁-C₆ alkyl optionally substituted with one or more NR⁸R⁹,        and R¹ is halo;    -   R² is C₁-C₆ alkyl optionally substituted with one or more oxo,        and R¹ is methyl; or    -   R² is C₁-C₆ alkyl optionally substituted with one or more C₁-C₆        alkoxy, and R¹ is C₁-C₆ alkyl.

In some embodiments, of the compound of formula AA,

the substituted ring A is

and R¹ and R² are one of the following combinations:

-   -   R¹ is 1-hydroxy-2-methylpropan-2-yl, and R² is methyl;    -   R¹ is 2-hydroxy-2-propyl and R² is methyl;    -   R¹ is 2-hydroxy-2-propyl and R² is isopropyl;    -   R¹ is 2-hydroxy-2-propyl and R² is 2-hydroxy-2-propyl;    -   R¹ is 2-hydroxy-2-propyl and R² is 1-hydroxyethyl;    -   R¹ is hydroxymethyl and R² is methyl;    -   R¹ is 1-hydroxyethyl and R² is methyl;    -   R¹ is 2-hydroxyethyl and R² is methyl;    -   R¹ is 1-hydroxy-2-propyl and R² is methyl;    -   R¹ is 2-hydroxy-2-propyl and R² is phenyl;    -   R¹ is 2-hydroxy-2-propyl and R² is pyridyl;    -   R¹ is 2-hydroxy-2-propyl and R² is pyrazolyl;    -   R¹ is 2-hydroxy-2-propyl, and R² is S(O₂)CH₃;    -   R¹ is 2-hydroxy-2-propyl and R² is chloro;    -   R¹ is 2-hydroxy-2-propyl and R² is fluoro;    -   R¹ is 1-hydroxy-1-cyclopropyl, and R² is methyl;    -   R¹ is 1-hydroxy-1-cyclobutyl, and R² is methyl;    -   R¹ is 1-hydroxy-1-cyclopentyl, and R² is methyl;    -   R¹ is 1-hydroxy-1-cyclohexyl, and R² is methyl;    -   R¹ is morpholinyl, and R² is methyl;    -   R¹ is 1,3-dioxolan-2-yl, and R² is methyl;    -   R¹ is 1,3-dioxolan-2-yl, and R² is fluoro;    -   R¹ is 1,3-dioxolan-2-yl, and R² is chloro;    -   R¹ is COCH₃, and R² is methyl;    -   R¹ is 2-methoxy-2-propyl, and R² is methyl;    -   R¹ is (dimethylamino)methyl, and R² is methyl.    -   R² is 1-hydroxy-2-methylpropan-2-yl, and R¹ is methyl;    -   R² is 2-hydroxy-2-propyl and R¹ is methyl;    -   R² is 2-hydroxy-2-propyl and R¹ is isopropyl;    -   R² is 2-hydroxy-2-propyl and R¹ is 1-hydroxyethyl;    -   R² is hydroxymethyl and R¹ is methyl;    -   R² is 1-hydroxyethyl and R¹ is methyl;    -   R² is 2-hydroxyethyl and R¹ is methyl;    -   R² is 1-hydroxy-2-propyl and R¹ is methyl;    -   R² is 2-hydroxy-2-propyl and R¹ is phenyl;    -   R² is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R¹ is 5- to 10-membered heteroaryl;    -   R² is 2-hydroxy-2-propyl and R¹ is pyridyl;    -   R² is 2-hydroxy-2-propyl and R¹ is pyrazolyl;    -   R² is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R¹ is S(O₂)CH₃;    -   R² is 2-hydroxy-2-propyl and R¹ is chloro;    -   R² is 2-hydroxy-2-propyl and R¹ is fluoro;    -   R² is C₃-C₇ cycloalkyl optionally substituted with one or more        hydroxy, and R¹ is C₁-C₆ alkyl;    -   R² is 1-hydroxy-1-cyclopropyl, and R¹ is methyl;    -   R² is 1-hydroxy-1-cyclobutyl, and R¹ is methyl;    -   R² is 1-hydroxy-1-cyclopentyl, and R¹ is methyl;    -   R² is 1-hydroxy-1-cyclohexyl, and R¹ is methyl;    -   R² is morpholinyl, and R¹ is methyl;    -   R² is 1,3-dioxolan-2-yl, and R¹ is methyl;    -   R² is 1,3-dioxolan-2-yl, and R¹ is fluoro;    -   R² is 1,3-dioxolan-2-yl, and R¹ is chloro;    -   R² is (dimethylamino)methyl, and R¹ is methyl;    -   R² is C₁-C₆ alkyl optionally substituted with one or more oxo,        and R¹ is methyl; or    -   R² is COCH₃, and R¹ is methyl.

In some embodiments, of the compound of formula AA,

the substituted ring A is

and R¹ and R² are one of the following combinations:

-   -   R¹ is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R² is C₁-C₆ alkyl optionally substituted with one        or more hydroxy;    -   R¹ is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R² is C₆-C₁₀ aryl;    -   R¹ is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R² is 5- to 10-membered heteroaryl;    -   R¹ is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R² is SF₅;    -   R¹ is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R² is S(O₂)C₁-C₆ alkyl;    -   R¹ is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R² is halo;    -   R¹ is C₃-C₇ cycloalkyl optionally substituted with one or more        hydroxy, and R² is C₁-C₆ alkyl;    -   R¹ is 3- to 7-membered heterocycloalkyl optionally substituted        with one or more hydroxy, and R² is C₁-C₆ alkyl;    -   R¹ is 3- to 7-membered heterocycloalkyl optionally substituted        with one or more hydroxy, and R² is halo;    -   R¹ is C₁-C₆ alkyl optionally substituted with one or more oxo,        and R² is methyl;    -   R¹ is C₁-C₆ alkyl optionally substituted with one or more C₁-C₆        alkoxy, and R² is C₁-C₆ alkyl;    -   R¹ is C₁-C₆ alkyl optionally substituted with one or more NR⁸R⁹,        and R² is C₁-C₆ alkyl;    -   R¹ is C₁-C₆ alkyl optionally substituted with one or more NR⁸R⁹,        and R² is halo;    -   R² is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R¹ is C₆-C₁₀ aryl;    -   R² is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R¹ is 5- to 10-membered heteroaryl;    -   R² is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R¹ is SF₅.    -   R² is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R¹ is S(O₂)C₁-C₆ alkyl;    -   R² is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R¹ is halo;    -   R² is C₃-C₇ cycloalkyl optionally substituted with one or more        hydroxy, and R¹ is C₁-C₆ alkyl;    -   R² is 3- to 7-membered heterocycloalkyl optionally substituted        with one or more hydroxy, and R¹ is C₁-C₆ alkyl;    -   R² is 3- to 7-membered heterocycloalkyl optionally substituted        with one or more hydroxy, and R¹ is halo;    -   R² is C₁-C₆ alkyl optionally substituted with one or more NR⁸R⁹,        and R¹ is C₁-C₆ alkyl;    -   R² is C₁-C₆ alkyl optionally substituted with one or more NR⁸R⁹,        and R¹ is halo;    -   R² is C₁-C₆ alkyl optionally substituted with one or more oxo,        and R¹ is methyl; or    -   R² is C₁-C₆ alkyl optionally substituted with one or more C₁-C₆        alkoxy, and R¹ is C₁-C₆ alkyl.

In some embodiments, of the compound of formula AA,

the substituted ring A is

and R¹ and R² are one of the following combinations:

-   -   R¹ is 1-hydroxy-2-methylpropan-2-yl, and R² is methyl;    -   R¹ is 2-hydroxy-2-propyl and R² is methyl;    -   R¹ is 2-hydroxy-2-propyl and R² is isopropyl;    -   R¹ is 2-hydroxy-2-propyl and R² is 2-hydroxy-2-propyl;    -   R¹ is 2-hydroxy-2-propyl and R² is 1-hydroxyethyl;    -   R¹ is hydroxymethyl and R² is methyl;    -   R¹ is 1-hydroxyethyl and R² is methyl;    -   R¹ is 2-hydroxyethyl and R² is methyl;    -   R¹ is 1-hydroxy-2-propyl and R² is methyl;    -   R¹ is 2-hydroxy-2-propyl and R² is phenyl;    -   R¹ is 2-hydroxy-2-propyl and R² is pyridyl;    -   R¹ is 2-hydroxy-2-propyl and R² is pyrazolyl;    -   R¹ is 2-hydroxy-2-propyl, and R² is S(O₂)CH₃;    -   R¹ is 2-hydroxy-2-propyl and R² is chloro;    -   R¹ is 2-hydroxy-2-propyl and R² is fluoro;    -   R¹ is 1-hydroxy-1-cyclopropyl, and R² is methyl;    -   R¹ is 1-hydroxy-1-cyclobutyl, and R² is methyl;    -   R¹ is 1-hydroxy-1-cyclopentyl, and R² is methyl;    -   R¹ is 1-hydroxy-1-cyclohexyl, and R² is methyl;    -   R¹ is morpholinyl, and R² is methyl;    -   R¹ is 1,3-dioxolan-2-yl, and R² is methyl;    -   R¹ is 1,3-dioxolan-2-yl, and R² is fluoro;    -   R¹ is 1,3-dioxolan-2-yl, and R² is chloro;    -   R¹ is COCH₃, and R² is methyl;    -   R¹ is 2-methoxy-2-propyl, and R² is methyl;    -   R¹ is C₁-C₆ alkyl optionally substituted with one or more NR⁸R⁹,        and R² is C₁-C₆ alkyl;    -   R¹ is C₁-C₆ alkyl optionally substituted with one or more NR⁸R⁹,        and R² is halo;    -   R² is 1-hydroxy-2-methylpropan-2-yl, and R¹ is methyl;    -   R² is 2-hydroxy-2-propyl and R¹ is methyl;    -   R² is 2-hydroxy-2-propyl and R¹ is isopropyl;    -   R² is 2-hydroxy-2-propyl and R¹ is 1-hydroxyethyl;    -   R² is hydroxymethyl and R¹ is methyl;    -   R² is 1-hydroxyethyl and R¹ is methyl;    -   R² is 2-hydroxyethyl and R¹ is methyl;    -   R² is 1-hydroxy-2-propyl and R¹ is methyl;    -   R² is 2-hydroxy-2-propyl and R¹ is phenyl;    -   R² is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R¹ is 5- to 10-membered heteroaryl;    -   R² is 2-hydroxy-2-propyl and R¹ is pyridyl;    -   R² is 2-hydroxy-2-propyl and R¹ is pyrazolyl;    -   R² is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R¹ is S(O₂)CH₃;    -   R² is 2-hydroxy-2-propyl and R¹ is chloro;    -   R² is 2-hydroxy-2-propyl and R¹ is fluoro;    -   R² is C₃-C₇ cycloalkyl optionally substituted with one or more        hydroxy, and R¹ is C₁-C₆ alkyl;    -   R² is 1-hydroxy-1-cyclopropyl, and R¹ is methyl;    -   R² is 1-hydroxy-1-cyclobutyl, and R¹ is methyl;    -   R² is 1-hydroxy-1-cyclopentyl, and R¹ is methyl;    -   R² is 1-hydroxy-1-cyclohexyl, and R¹ is methyl;    -   R² is morpholinyl, and R¹ is methyl;    -   R² is 1,3-dioxolan-2-yl, and R¹ is methyl;    -   R² is 1,3-dioxolan-2-yl, and R¹ is fluoro;    -   R² is 1,3-dioxolan-2-yl, and R¹ is chloro;    -   R² is C₁-C₆ alkyl optionally substituted with one or more oxo,        and R¹ is methyl;    -   R² is C₁-C₆ alkyl optionally substituted with one or more NR⁸R⁹,        and R¹ is C₁-C₆ alkyl;    -   R² is C₁-C₆ alkyl optionally substituted with one or more NR⁸R⁹,        and R¹ is halo;    -   R² is COCH₃, and R¹ is methyl; or    -   R² is 2-methoxy-2-propyl, and R¹ is methyl.

In some embodiments, of the compound of formula AA,

the substituted ring A is

and R¹ and R² are one of the following combinations:

-   -   R¹ is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R² is C₁-C₆ alkyl optionally substituted with one        or more hydroxy;    -   R¹ is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R² is C₆-C₁₀ aryl;    -   R¹ is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R² is 5- to 10-membered heteroaryl;    -   R¹ is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R² is SF₅;    -   R¹ is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R² is S(O₂)C₁-C₆ alkyl;    -   R¹ is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R² is halo;    -   R¹ is C₃-C₇ cycloalkyl optionally substituted with one or more        hydroxy, and R² is C₁-C₆ alkyl;    -   R¹ is 3- to 7-membered heterocycloalkyl optionally substituted        with one or more hydroxy, and R² is C₁-C₆ alkyl;    -   R¹ is 3- to 7-membered heterocycloalkyl optionally substituted        with one or more hydroxy, and R² is halo;    -   R¹ is C₁-C₆ alkyl optionally substituted with one or more oxo,        and R² is methyl;    -   R¹ is C₁-C₆ alkyl optionally substituted with one or more C₁-C₆        alkoxy, and R² is C₁-C₆ alkyl;    -   R¹ is C₁-C₆ alkyl optionally substituted with one or more NR⁸R⁹,        and R² is C₁-C₆ alkyl;    -   R¹ is C₁-C₆ alkyl optionally substituted with one or more NR⁸R⁹,        and R² is halo;    -   R² is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R¹ is C₆-C₁₀ aryl;    -   R² is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R¹ is 5- to 10-membered heteroaryl;    -   R² is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R¹ is SF₅.    -   R² is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R¹ is S(O₂)C₁-C₆ alkyl;    -   R² is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R¹ is halo;    -   R² is C₃-C₇ cycloalkyl optionally substituted with one or more        hydroxy, and R¹ is C₁-C₆ alkyl;    -   R² is 3- to 7-membered heterocycloalkyl optionally substituted        with one or more hydroxy, and R¹ is C₁-C₆ alkyl;    -   R² is 3- to 7-membered heterocycloalkyl optionally substituted        with one or more hydroxy, and R¹ is halo;    -   R² is C₁-C₆ alkyl optionally substituted with one or more NR⁸R⁹,        and R¹ is C₁-C₆ alkyl;    -   R² is C₁-C₆ alkyl optionally substituted with one or more NR⁸R⁹,        and R¹ is halo;    -   R² is C₁-C₆ alkyl optionally substituted with one or more oxo,        and R¹ is methyl; or    -   R² is C₁-C₆ alkyl optionally substituted with one or more C₁-C₆        alkoxy, and R¹ is C₁-C₆ alkyl.

In some embodiments, of the compound of formula AA,

the substituted ring A is

and R¹ and R² are one of the following combinations:

-   -   R¹ is 1-hydroxy-2-methylpropan-2-yl, and R² is methyl;    -   R¹ is 2-hydroxy-2-propyl and R² is methyl;    -   R¹ is 2-hydroxy-2-propyl and R² is isopropyl;    -   R¹ is 2-hydroxy-2-propyl and R² is 2-hydroxy-2-propyl;    -   R¹ is 2-hydroxy-2-propyl and R² is 1-hydroxyethyl;    -   R¹ is hydroxymethyl and R² is methyl;    -   R¹ is 1-hydroxyethyl and R² is methyl;    -   R¹ is 2-hydroxyethyl and R² is methyl;    -   R¹ is 1-hydroxy-2-propyl and R² is methyl;    -   R¹ is 2-hydroxy-2-propyl and R² is phenyl;    -   R¹ is 2-hydroxy-2-propyl and R² is pyridyl;    -   R¹ is 2-hydroxy-2-propyl and R² is pyrazolyl;    -   R¹ is 2-hydroxy-2-propyl, and R² is S(O₂)CH₃;    -   R¹ is 2-hydroxy-2-propyl and R² is chloro;    -   R¹ is 2-hydroxy-2-propyl and R² is fluoro;    -   R¹ is 1-hydroxy-1-cyclopropyl, and R² is methyl;    -   R¹ is 1-hydroxy-1-cyclobutyl, and R² is methyl;    -   R¹ is 1-hydroxy-1-cyclopentyl, and R² is methyl;    -   R¹ is 1-hydroxy-1-cyclohexyl, and R² is methyl;    -   R¹ is morpholinyl, and R² is methyl;    -   R¹ is 1,3-dioxolan-2-yl, and R² is methyl;    -   R¹ is 1,3-dioxolan-2-yl, and R² is fluoro;    -   R¹ is 1,3-dioxolan-2-yl, and R² is chloro;    -   R¹ is COCH₃, and R² is methyl;    -   R¹ is 2-methoxy-2-propyl, and R² is methyl;    -   R¹ is (dimethylamino)methyl, and R² is methyl.    -   R² is 1-hydroxy-2-methylpropan-2-yl, and R¹ is methyl;    -   R² is 2-hydroxy-2-propyl and R¹ is methyl;    -   R² is 2-hydroxy-2-propyl and R¹ is isopropyl;    -   R² is 2-hydroxy-2-propyl and R¹ is 1-hydroxyethyl;    -   R² is hydroxymethyl and R¹ is methyl;    -   R² is 1-hydroxyethyl and R¹ is methyl;    -   R² is 2-hydroxyethyl and R¹ is methyl;    -   R² is 1-hydroxy-2-propyl and R¹ is methyl;    -   R² is 2-hydroxy-2-propyl and R¹ is phenyl;    -   R² is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R¹ is 5- to 10-membered heteroaryl;    -   R² is 2-hydroxy-2-propyl and R¹ is pyridyl;    -   R² is 2-hydroxy-2-propyl and R¹ is pyrazolyl;    -   R² is C₁-C₆ alkyl optionally substituted with one or more        hydroxy, and R¹ is S(O₂)CH₃;    -   R² is 2-hydroxy-2-propyl and R¹ is chloro;    -   R² is 2-hydroxy-2-propyl and R¹ is fluoro;    -   R² is C₃-C₇ cycloalkyl optionally substituted with one or more        hydroxy, and R¹ is C₁-C₆ alkyl;    -   R² is 1-hydroxy-1-cyclopropyl, and R¹ is methyl;    -   R² is 1-hydroxy-1-cyclobutyl, and R¹ is methyl;    -   R² is 1-hydroxy-1-cyclopentyl, and R¹ is methyl;    -   R² is 1-hydroxy-1-cyclohexyl, and R¹ is methyl;    -   R² is morpholinyl, and R¹ is methyl;    -   R² is 1,3-dioxolan-2-yl, and R¹ is methyl;    -   R² is 1,3-dioxolan-2-yl, and R¹ is fluoro;    -   R² is 1,3-dioxolan-2-yl, and R¹ is chloro;    -   R² is C₁-C₆ alkyl optionally substituted with one or more oxo,        and R¹ is methyl;    -   R² is (dimethylamino)methyl, and R¹ is methyl;    -   R² is COCH₃, and R¹ is methyl; or    -   R² is 2-methoxy-2-propyl, and R¹ is methyl.

In some embodiments of the compound of formula AA,

the substituted ring B is

and R⁶ is selected from:

-   -   C₁-C₆ alkyl, C₁-C₆ alkyl substituted with one or more halo,        C₁-C₆ alkoxy, C₁-C₆ alkoxy substituted with one or more halo,        C₃-C₇ cycloalkyl, halo, and cyano.

In some embodiments of the compound of formula AA,

the substituted ring B is

and R⁶ is selected from:

-   -   isopropyl, ethyl, methyl, trifluoromethyl, trifluoromethoxy,        cyclopropyl, halo, chloro, and fluoro.

In some embodiments of the compound of formula AA,

the substituted ring B is

and R⁶ is selected from:

-   -   C₁-C₆ alkyl, C₁-C₆ alkyl substituted with one or more halo,        C₁-C₆ alkoxy, C₁-C₆ alkoxy substituted with one or more halo,        C₃-C₇ cycloalkyl, halo, and cyano.

In some embodiments of the compound of formula AA,

the substituted ring B is

and R⁶ is selected from:

-   -   isopropyl, ethyl, methyl, trifluoromethyl, trifluoromethoxy,        cyclopropyl, halo, chloro, and fluoro.

In some embodiments of the compound of formula AA,

the substituted ring B is

and R⁶ is selected from:

-   -   C₁-C₆ alkyl, C₁-C₆ alkyl substituted with one or more halo,        C₁-C₆ alkoxy, C₁-C₆ alkoxy substituted with one or more halo,        C₃-C₇ cycloalkyl, halo, and cyano.

In some embodiments of the compound of formula AA,

the substituted ring B is

and R⁶ is selected from:

-   -   isopropyl, ethyl, methyl, trifluoromethyl, trifluoromethoxy,        cyclopropyl, halo, chloro, and fluoro.

In some embodiments of the compound of formula AA,

the substituted ring B is

and R⁶ is selected from:

-   -   C₁-C₆ alkyl, C₁-C₆ alkyl substituted with one or more halo,        C₁-C₆ alkoxy, C₁-C₆ alkoxy substituted with one or more halo,        C₃-C₇ cycloalkyl, halo, and cyano.

In some embodiments of the compound of formula AA,

the substituted ring B is

and R⁶ is selected from:

-   -   isopropyl, ethyl, methyl, trifluoromethyl, trifluoromethoxy,        cyclopropyl, halo, chloro, and fluoro.

In some embodiments of the compound of formula AA,

the substituted ring B is

and R⁶ is selected from:

-   -   C₁-C₆ alkyl, C₁-C₆ alkyl substituted with one or more halo,        C₁-C₆ alkoxy, C₁-C₆ alkoxy substituted with one or more halo,        C₃-C₇ cycloalkyl, halo, and cyano.

In some embodiments of the compound of formula AA,

the substituted ring B is

and R⁶ is selected from:

-   -   isopropyl, ethyl, methyl, trifluoromethyl, trifluoromethoxy,        cyclopropyl, halo, chloro, and fluoro.

In some embodiments, of the compound of formula AA,

the substituted ring B is

and the two R⁶ are one of the following combinations:

-   -   (i) One R⁶ is C₁-C₆ alkyl, and the other R⁶ is C₁-C₆ alkyl        optionally substituted with one or more halo;    -   (ii) One R⁶ is C₁-C₆ alkyl and the other R⁶ is C₁-C₆ alkyl;    -   (iii) One R⁶ is C₁-C₆ alkyl, and the other R⁶ is C₁-C₆ alkyl        substituted with one or more halo;    -   (iv) One R⁶ is C₁-C₆ alkyl, and the other R⁶ is C₃-C₇        cycloalkyl;    -   (v) One R⁶ is C₁-C₆ alkyl, and the other R⁶ is halo;    -   (vi) One R⁶ is C₁-C₆ alkyl, and the other R⁶ is cyano;    -   (vii) One R⁶ is C₃-C₇ cycloalkyl, and the other R⁶ is C₃-C₇        cycloalkyl;    -   (viii) One R⁶ is C₃-C₇ cycloalkyl, and the other R⁶ is halo;    -   (ix) One R⁶ is cyclopropyl and the other R⁶ is halo;    -   (x) One R⁶ is C₁-C₆ alkyl, and the other R⁶ is C₁-C₆ alkoxy        optionally substituted with one or more halo;    -   (xi) One R⁶ is C₁-C₆ alkyl, and the other R⁶ is C₁-C₆ alkoxy;    -   (xii) One R⁶ is C₁-C₆ alkyl, and the other R⁶ is C₁-C₆ alkoxy        substituted with one or more halo;    -   (xiii) One R⁶ is halo, and the other R⁶ is C₁-C₆ haloalkyl;    -   (xiv) One R⁶ is halo, and the other R⁶ is C₁-C₆ haloalkoxy;    -   (xv) One R⁶ is C₁-C₆ alkoxy; and the other R⁶ is halo;    -   (xvi) One R⁶ is C₁-C₆ alkoxy; and the other R⁶ is chloro.

In some embodiments, of the compound of formula AA,

the substituted ring B is

and the two R⁶ are one of the following combinations:

-   -   (i) One R⁶ is isopropyl; and the other R⁶ is methyl;    -   (ii) One R⁶ is isopropyl; and the other R⁶ is n-propyl;    -   (iii) One R⁶ is isopropyl; and the other R⁶ is isopropyl;    -   (iv) One R⁶ is isopropyl; and the other R⁶ is trifluoromethyl;    -   (v) One R⁶ is isopropyl; and the other R⁶ is cyclopropyl;    -   (vi) One R⁶ is isopropyl; and the other R⁶ is chloro;    -   (vii) One R⁶ is isopropyl; and the other R⁶ is fluoro;    -   (viii) One R⁶ is ethyl; and the other R⁶ is fluoro;    -   (ix) One R⁶ is isopropyl; and the other R⁶ is cyano;    -   (x) One R⁶ is cyclopropyl; and the other R⁶ is cyclopropyl;    -   (xi) One R⁶ is cyclopropyl; and the other R⁶ is chloro;    -   (xii) One R⁶ is cyclopropyl; and the other R⁶ is fluoro;    -   (xiii) One R⁶ is isopropyl; and the other R⁶ is methoxy;    -   (xiv) One R⁶ is isopropyl; and the other R⁶ is methoxy; or    -   (xv) One R⁶ is isopropyl; and the other R⁶ is trifluoromethoxy.

In some embodiments, of the compound of formula AA,

the substituted ring B is

and R⁶ and R⁷ are one of the following combinations:

-   -   (i) R⁶ is C₁-C₆ alkyl, and R⁷ is C₁-C₆ alkyl optionally        substituted with one or more halo;    -   (ii) R⁶ is C₁-C₆ alkyl and R⁷ is C₁-C₆ alkyl;    -   (iii) R⁶ is C₁-C₆ alkyl, and R⁷ is C₁-C₆ alkyl substituted with        one or more halo;    -   (iv) R⁶ is C₁-C₆ alkyl, and R⁷ is C₃-C₇ cycloalkyl;    -   (v) R⁶ is C₁-C₆ alkyl, and R⁷ is halo;    -   (vi) R⁶ is C₁-C₆ alkyl, and R⁷ is cyano;    -   (vii) R⁶ is C₃-C₇ cycloalkyl, and R⁷ is C₃-C₇ cycloalkyl;    -   (viii) R⁶ is C₃-C₇ cycloalkyl, and R⁷ is halo;    -   (ix) R⁶ is cyclopropyl and R⁷ is halo;    -   (x) R⁶ is C₁-C₆ alkyl, and R⁷ is C₁-C₆ alkoxy optionally        substituted with one or more halo;    -   (xi) R⁶ is C₁-C₆ alkyl, and R⁷ is C₁-C₆ alkoxy;    -   (xii) R⁶ is C₁-C₆ alkyl, and R⁷ is C₁-C₆ alkoxy substituted with        one or more halo;    -   (xiii) R⁶ is halo, and R⁷ is C₁-C₆ haloalkyl;    -   (xiv) R⁶ is halo, and R⁷ is C₁-C₆ haloalkoxy;    -   (xv) R⁶ is C₁-C₆ alkoxy; and R⁷ is halo;    -   (xvi) R⁶ is C₁-C₆ alkoxy; and R⁷ is chloro;    -   (xvii) R⁷ is C₁-C₆ alkyl, and R⁶ is C₁-C₆ alkyl optionally        substituted with one or more halo;    -   (xviii) R⁷ is C₁-C₆ alkyl, and R⁶ is C₁-C₆ alkyl substituted        with one or more halo;    -   (xix) R⁷ is C₁-C₆ alkyl, and R⁶ is C₃-C₇ cycloalkyl;    -   (xx) R⁷ is C₁-C₆ alkyl, and R⁶ is halo;    -   (xxi) R⁷ is C₁-C₆ alkyl and R⁶ is halo;    -   (xxii) R⁷ is C₁-C₆ alkyl, and R⁶ is cyano;    -   (xxiii) R⁷ is C₃-C₇ cycloalkyl, and R⁶ is C₃-C₇ cycloalkyl;    -   (xxiv) R⁷ is C₃-C₇ cycloalkyl, and R⁶ is halo;    -   (xxv) R⁷ is C₃-C₇ cycloalkyl and R⁶ is halo;    -   (xxvi) R⁷ is C₁-C₆ alkyl, and R⁶ is C₁-C₆ alkoxy optionally        substituted with one or more halo;    -   (xxvii) R⁷ is C₁-C₆ alkyl, and R⁶ is C₁-C₆ alkoxy;    -   (xxviii) R⁷ is C₁-C₆ alkyl, and R⁶ is C₁-C₆ alkoxy substituted        with one or more halo;    -   (xxix) R⁷ is halo, and R⁶ is C₁-C₆ haloalkyl;    -   (xxx) R⁷ is halo, and R⁶ is C₁-C₆ haloalkoxy;    -   (xxxi) R⁷ is C₁-C₆ alkoxy; and R⁶ is halo; or    -   (xxxii) R⁷ is C₁-C₆ alkoxy; and R⁶ is chloro.

In some embodiments, of the compound of formula AA,

the substituted ring B is

and R⁶ and R⁷ are one of the following combinations:

-   -   (i) R⁶ is isopropyl; and R⁷ is methyl;    -   (ii) R⁶ is isopropyl; and R⁷ is isopropyl;    -   (iii) R⁶ is isopropyl; and R⁷ is trifluoromethyl;    -   (iv) R⁶ is isopropyl; and R⁷ is cyclopropyl;    -   (v) R⁶ is isopropyl; and R⁷ is chloro;    -   (vi) R⁶ is isopropyl; and R⁷ is fluoro;    -   (vii) R⁶ is ethyl; and R⁷ is fluoro;    -   (viii) R⁶ is isopropyl; and R⁷ is cyano;    -   (ix) R⁶ is cyclopropyl; and R⁷ is cyclopropyl;    -   (x) R⁶ is cyclopropyl; and R⁷ is chloro;    -   (xi) R⁶ is cyclopropyl; and R⁷ is fluoro; R⁶ is isopropyl; and        R⁷ is methoxy;    -   (xii) R⁶ is isopropyl; and R⁷ is trifluoromethoxy;    -   (xiii) R⁶ is chloro; and R⁷ is trifluoromethyl;    -   (xiv) R⁶ is chloro; and R⁷ is trifluoromethoxy;    -   (xv) R⁷ is isopropyl; and R⁶ is methyl;    -   (xvi) R⁷ is isopropyl; and R⁶ is trifluoromethyl;    -   (xvii) R⁷ is isopropyl; and R⁶ is cyclopropyl;    -   (xviii) R⁷ is isopropyl; and R⁶ is chloro;    -   (xix) R⁷ is ethyl; and R⁶ is fluoro;    -   (xx) R⁷ is isopropyl; and R⁶ is cyano;    -   (xxi) R⁷ is cyclopropyl; and R⁶ is cyclopropyl;    -   (xxii) R⁷ is cyclopropyl; and R⁶ is chloro;    -   (xxiii) R⁷ is cyclopropyl; and R⁶ is fluoro;    -   (xxiv) R⁷ is isopropyl; and R⁶ is methoxy;    -   (xxv) R⁷ is isopropyl; and R⁶ is trifluoromethoxy;    -   (xxvi) R⁷ is chloro; and R⁶ is trifluoromethyl; or    -   (xxvii) R⁷ is chloro; and R⁶ is trifluoromethoxy.

In some embodiments, of the compound of formula AA,

the substituted ring B is

and R⁶ and R⁷ are one of the following combinations:

-   -   (i) R⁶ is C₁-C₆ alkyl, and R⁷ is C₁-C₆ alkyl optionally        substituted with one or more halo;    -   (ii) R⁶ is C₁-C₆ alkyl and R⁷ is C₁-C₆ alkyl;    -   (iii) R⁶ is C₁-C₆ alkyl, and R⁷ is C₁-C₆ alkyl substituted with        one or more halo;    -   (iv) R⁶ is C₁-C₆ alkyl, and R⁷ is C₃-C₇ cycloalkyl;    -   (v) R⁶ is C₁-C₆ alkyl, and R⁷ is halo;    -   (vi) R⁶ is C₁-C₆ alkyl, and R⁷ is cyano;    -   (vii) R⁶ is C₃-C₇ cycloalkyl, and R⁷ is C₃-C₇ cycloalkyl;    -   (viii) R⁶ is C₃-C₇ cycloalkyl, and R⁷ is halo;    -   (ix) R⁶ is cyclopropyl and R⁷ is halo;    -   (x) R⁶ is C₁-C₆ alkyl, and R⁷ is C₁-C₆ alkoxy optionally        substituted with one or more halo;    -   (xi) R⁶ is C₁-C₆ alkyl, and R⁷ is C₁-C₆ alkoxy;    -   (xii) R⁶ is C₁-C₆ alkyl, and R⁷ is C₁-C₆ alkoxy substituted with        one or more halo;    -   (xiii) R⁶ is halo, and R⁷ is C₁-C₆ haloalkyl;    -   (xiv) R⁶ is halo, and R⁷ is C₁-C₆ haloalkoxy;    -   (xv) R⁶ is C₁-C₆ alkoxy; and R⁷ is halo;    -   (xvi) R⁶ is C₁-C₆ alkoxy; and R⁷ is chloro;    -   (xvii) R⁷ is C₁-C₆ alkyl, and R⁶ is C₁-C₆ alkyl optionally        substituted with one or more halo;    -   (xviii) R⁷ is C₁-C₆ alkyl, and R⁶ is C₁-C₆ alkyl substituted        with one or more halo;    -   (xix) R⁷ is C₁-C₆ alkyl, and R⁶ is C₃-C₇ cycloalkyl;    -   (xx) R⁷ is C₁-C₆ alkyl, and R⁶ is halo;    -   (xxi) R⁷ is C₁-C₆ alkyl and R⁶ is halo;    -   (xxii) R⁷ is C₁-C₆ alkyl, and R⁶ is cyano;    -   (xxiii) R⁷ is C₃-C₇ cycloalkyl, and R⁶ is C₃-C₇ cycloalkyl;    -   (xxiv) R⁷ is C₃-C₇ cycloalkyl, and R⁶ is halo;    -   (xxv) R⁷ is C₃-C₇ cycloalkyl and R⁶ is halo;    -   (xxvi) R⁷ is C₁-C₆ alkyl, and R⁶ is C₁-C₆ alkoxy optionally        substituted with one or more halo;    -   (xxvii) R⁷ is C₁-C₆ alkyl, and R⁶ is C₁-C₆ alkoxy;    -   (xxviii) R⁷ is C₁-C₆ alkyl, and R⁶ is C₁-C₆ alkoxy substituted        with one or more halo;    -   (xxix) R⁷ is halo, and R⁶ is C₁-C₆ haloalkyl;    -   (xxx) R⁷ is halo, and R⁶ is C₁-C₆ haloalkoxy;    -   (xxxi) R⁷ is C₁-C₆ alkoxy; and R⁶ is halo; or    -   (xxxii) R⁷ is C₁-C₆ alkoxy; and R⁶ is chloro.

In some embodiments, of the compound of formula AA,

the substituted ring B is

and R⁶ and R⁷ are one of the following combinations:

-   -   (i) R⁶ is isopropyl; and R⁷ is methyl;    -   (ii) R⁶ is isopropyl; and R⁷ is isopropyl;    -   (iii) R⁶ is isopropyl; and R⁷ is trifluoromethyl;    -   (iv) R⁶ is isopropyl; and R⁷ is cyclopropyl;    -   (v) R⁶ is isopropyl; and R⁷ is chloro;    -   (vi) R⁶ is isopropyl; and R⁷ is fluoro;    -   (vii) R⁶ is ethyl; and R⁷ is fluoro;    -   (viii) R⁶ is isopropyl; and R⁷ is cyano;    -   (ix) R⁶ is cyclopropyl; and R⁷ is cyclopropyl;    -   (x) R⁶ is cyclopropyl; and R⁷ is chloro;    -   (xi) R⁶ is cyclopropyl; and R⁷ is fluoro;    -   (xii) R⁶ is isopropyl; and R⁷ is methoxy;    -   (xiii) R⁶ is isopropyl; and R⁷ is trifluoromethoxy;    -   (xiv) R⁶ is chloro; and R⁷ is trifluoromethyl;    -   (xv) R⁶ is chloro; and R⁷ is trifluoromethoxy;    -   (xvi) R⁷ is isopropyl; and R⁶ is methyl;    -   (xvii) R⁷ is isopropyl; and R⁶ is trifluoromethyl;    -   (xviii) R⁷ is isopropyl; and R⁶ is cyclopropyl;    -   (xix) R⁷ is isopropyl; and R⁶ is chloro;    -   (xx) R⁷ is ethyl; and R⁶ is fluoro;    -   (xxi) R⁷ is isopropyl; and R⁶ is cyano;    -   (xxii) R⁷ is cyclopropyl; and R⁶ is cyclopropyl;    -   (xxiii) R⁷ is cyclopropyl; and R⁶ is chloro;    -   (xxiv) R⁷ is cyclopropyl; and R⁶ is fluoro;    -   (xxv) R⁷ is isopropyl; and R⁶ is methoxy;    -   (xxvi) R⁷ is isopropyl; and R⁶ is trifluoromethoxy;    -   (xxvii) R⁷ is chloro; and R⁶ is trifluoromethyl; or    -   (xxviii) R⁷ is chloro; and R⁶ is trifluoromethoxy.

In some embodiments, of the compound of formula AA,

the substituted ring B is

and R⁶ and R⁷ are one of the following combinations:

-   -   (i) R⁶ is C₁-C₆ alkyl, and R⁷ is C₁-C₆ alkyl optionally        substituted with one or more halo;    -   (ii) R⁶ is C₁-C₆ alkyl and R⁷ is C₁-C₆ alkyl;    -   (iii) R⁶ is C₁-C₆ alkyl, and R⁷ is C₁-C₆ alkyl substituted with        one or more halo;    -   (iv) R⁶ is C₁-C₆ alkyl, and R⁷ is C₃-C₇ cycloalkyl;    -   (v) R⁶ is C₁-C₆ alkyl, and R⁷ is halo;    -   (vi) R⁶ is C₁-C₆ alkyl, and R⁷ is cyano;    -   (vii) R⁶ is C₃-C₇ cycloalkyl, and R⁷ is C₃-C₇ cycloalkyl;    -   (viii) R⁶ is C₃-C₇ cycloalkyl, and R⁷ is halo;    -   (ix) R⁶ is cyclopropyl and R⁷ is halo;    -   (x) R⁶ is C₁-C₆ alkyl, and R⁷ is C₁-C₆ alkoxy optionally        substituted with one or more halo;    -   (xi) R⁶ is C₁-C₆ alkyl, and R⁷ is C₁-C₆ alkoxy;    -   (xii) R⁶ is C₁-C₆ alkyl, and R⁷ is C₁-C₆ alkoxy substituted with        one or more halo;    -   (xiii) R⁶ is halo, and R⁷ is C₁-C₆ haloalkyl;    -   (xiv) R⁶ is halo, and R⁷ is C₁-C₆ haloalkoxy;    -   (xv) R⁶ is C₁-C₆ alkoxy; and R⁷ is halo;    -   (xvi) R⁶ is C₁-C₆ alkoxy; and R⁷ is chloro;    -   (xvii) R⁷ is C₁-C₆ alkyl, and R⁶ is C₁-C₆ alkyl optionally        substituted with one or more halo;    -   (xviii) R⁷ is C₁-C₆ alkyl, and R⁶ is C₁-C₆ alkyl substituted        with one or more halo;    -   (xix) R⁷ is C₁-C₆ alkyl, and R⁶ is C₃-C₇ cycloalkyl;    -   (xx) R⁷ is C₁-C₆ alkyl, and R⁶ is halo;    -   (xxi) R⁷ is C₁-C₆ alkyl and R⁶ is halo;    -   (xxii) R⁷ is C₁-C₆ alkyl, and R⁶ is cyano;    -   (xxiii) R⁷ is C₃-C₇ cycloalkyl, and R⁶ is C₃-C₇ cycloalkyl;    -   (xxiv) R⁷ is C₃-C₇ cycloalkyl, and R⁶ is halo;    -   (xxv) R⁷ is C₃-C₇ cycloalkyl and R⁶ is halo;    -   (xxvi) R⁷ is C₁-C₆ alkyl, and R⁶ is C₁-C₆ alkoxy optionally        substituted with one or more halo;    -   (xxvii) R⁷ is C₁-C₆ alkyl, and R⁶ is C₁-C₆ alkoxy;    -   (xxviii) R⁷ is C₁-C₆ alkyl, and R⁶ is C₁-C₆ alkoxy substituted        with one or more halo;    -   (xxix) R⁷ is halo, and R⁶ is C₁-C₆ haloalkyl;    -   (xxx) R⁷ is halo, and R⁶ is C₁-C₆ haloalkoxy;    -   (xxxi) R⁷ is C₁-C₆ alkoxy; and R⁶ is halo; or    -   (xxxii) R⁷ is C₁-C₆ alkoxy; and R⁶ is chloro;    -   (xxxiii) R⁶ and R⁷ on adjacent atoms taken together with the        atoms connecting them form a C₄-C₆ aliphatic carbocyclic ring        optionally substituted with one or more hydroxy, oxo, or C₁-C₆        alkyl; or    -   (xxxiv) R⁶ and R⁷ on adjacent atoms taken together with the        atoms connecting them form a 5-to-6-membered heterocyclic ring        containing 1 heteroatom independently selected from O, N, and S,        wherein the heterocyclic ring optionally substituted with one or        more hydroxy, oxo, or C₁-C₆ alkyl.

In some embodiments, of the compound of formula AA,

the substituted ring B is

and R⁶ and R⁷ are one of the following combinations:

-   -   (i) R⁶ is isopropyl; and R⁷ is methyl;    -   (ii) R⁶ is isopropyl; and R⁷ is isopropyl;    -   (iii) R⁶ is isopropyl; and R⁷ is trifluoromethyl;    -   (iv) R⁶ is isopropyl; and R⁷ is cyclopropyl;    -   (v) R⁶ is isopropyl; and R⁷ is chloro;    -   (vi) R⁶ is isopropyl; and R⁷ is fluoro;    -   (vii) R⁶ is ethyl; and R⁷ is fluoro;    -   (viii) R⁶ is isopropyl; and R⁷ is cyano;    -   (ix) R⁶ is cyclopropyl; and R⁷ is cyclopropyl;    -   (x) R⁶ is cyclopropyl; and R⁷ is chloro;    -   (xi) R⁶ is cyclopropyl; and R⁷ is fluoro;    -   (xii) R⁶ is isopropyl; and R⁷ is methoxy;    -   (xiii) R⁶ is isopropyl; and R⁷ is trifluoromethoxy;    -   (xiv) R⁶ is chloro; and R⁷ is trifluoromethyl;    -   (xv) R⁶ is chloro; and R⁷ is trifluoromethoxy;    -   (xvi) R⁷ is isopropyl; and R⁶ is methyl;    -   (xvii) R⁷ is isopropyl; and R⁶ is trifluoromethyl;    -   (xviii) R⁷ is isopropyl; and R⁶ is cyclopropyl;    -   (xix) R⁷ is isopropyl; and R⁶ is chloro;    -   (xx) R⁷ is ethyl; and R⁶ is fluoro;    -   (xxi) R⁷ is isopropyl; and R⁶ is cyano;    -   (xxii) R⁷ is cyclopropyl; and R⁶ is cyclopropyl;    -   (xxiii) R⁷ is cyclopropyl; and R⁶ is chloro;    -   (xxiv) R⁷ is cyclopropyl; and R⁶ is fluoro;    -   (xxv) R⁷ is isopropyl; and R⁶ is methoxy;    -   (xxvi) R⁷ is isopropyl; and R⁶ is trifluoromethoxy;    -   (xxvii) R⁷ is chloro; and R⁶ is trifluoromethyl;    -   (xxviii) R⁷ is chloro; and R⁶ is trifluoromethoxy;    -   (xxix) R⁶ and R⁷ on adjacent atoms taken together with the atoms        connecting them form a C₄ aliphatic carbocyclic ring;    -   (xxx) R⁶ and R⁷ on adjacent atoms taken together with the atoms        connecting them form a C₅ aliphatic carbocyclic ring;    -   (xxxi) R⁶ and R⁷ on adjacent atoms taken together with the atoms        connecting them form a C₆ aliphatic carbocyclic ring;    -   (xxxii) R⁶ and R⁷ on adjacent atoms taken together with the        atoms connecting them form a 5-membered heterocyclic ring        containing 1 heteroatoms independently selected from 0, N, and        S;    -   (xxxiii) R⁶ and R⁷ on adjacent atoms taken together with the        atoms connecting them form a 6-membered heterocyclic ring        containing 1 heteroatoms independently selected from 0, N, and        S; or    -   (xxxiv) R⁶ and R⁷ on adjacent atoms taken together with the        atoms connecting them form a C₅ aliphatic carbocyclic ring.

In some embodiments, of the compound of formula AA,

the substituted ring B is

and R⁶ and R⁷ are one of the following combinations:

-   -   (i) R⁶ is C₁-C₆ alkyl, and R⁷ is C₁-C₆ alkyl optionally        substituted with one or more halo;    -   (ii) R⁶ is C₁-C₆ alkyl and R⁷ is C₁-C₆ alkyl;    -   (iii) R⁶ is C₁-C₆ alkyl, and R⁷ is C₁-C₆ alkyl substituted with        one or more halo;    -   (iv) R⁶ is C₁-C₆ alkyl, and R⁷ is C₃-C₇ cycloalkyl;    -   (v) R⁶ is C₁-C₆ alkyl, and R⁷ is halo;    -   (vi) R⁶ is C₁-C₆ alkyl, and R⁷ is cyano;    -   (vii) R⁶ is C₃-C₇ cycloalkyl, and R⁷ is C₃-C₇ cycloalkyl;    -   (viii) R⁶ is C₃-C₇ cycloalkyl, and R⁷ is halo;    -   (ix) R⁶ is cyclopropyl and R⁷ is halo;    -   (x) R⁶ is C₁-C₆ alkyl, and R⁷ is C₁-C₆ alkoxy optionally        substituted with one or more halo;    -   (xi) R⁶ is C₁-C₆ alkyl, and R⁷ is C₁-C₆ alkoxy;    -   (xii) R⁶ is C₁-C₆ alkyl, and R⁷ is C₁-C₆ alkoxy substituted with        one or more halo;    -   (xiii) R⁶ is halo, and R⁷ is C₁-C₆ haloalkyl;    -   (xiv) R⁶ is halo, and R⁷ is C₁-C₆ haloalkoxy;    -   (xv) R⁶ is C₁-C₆ alkoxy; and R⁷ is halo;    -   (xvi) R⁶ is C₁-C₆ alkoxy; and R⁷ is chloro;    -   (xvii) R⁷ is C₁-C₆ alkyl, and R⁶ is C₁-C₆ alkyl optionally        substituted with one or more halo;    -   (xviii) R⁷ is C₁-C₆ alkyl, and R⁶ is C₁-C₆ alkyl substituted        with one or more halo;    -   (xix) R⁷ is C₁-C₆ alkyl, and R⁶ is C₃-C₇ cycloalkyl;    -   (xx) R⁷ is C₁-C₆ alkyl, and R⁶ is halo;    -   (xxi) R⁷ is C₁-C₆ alkyl and R⁶ is halo;    -   (xxii) R⁷ is C₁-C₆ alkyl, and R⁶ is cyano;    -   (xxiii) R⁷ is C₃-C₇ cycloalkyl, and R⁶ is C₃-C₇ cycloalkyl;    -   (xxiv) R⁷ is C₃-C₇ cycloalkyl, and R⁶ is halo;    -   (xxv) R⁷ is C₃-C₇ cycloalkyl and R⁶ is halo;    -   (xxvi) R⁷ is C₁-C₆ alkyl, and R⁶ is C₁-C₆ alkoxy optionally        substituted with one or more halo;    -   (xxvii) R⁷ is C₁-C₆ alkyl, and R⁶ is C₁-C₆ alkoxy;    -   (xxviii) R⁷ is C₁-C₆ alkyl, and R⁶ is C₁-C₆ alkoxy substituted        with one or more halo;    -   (xxix) R⁷ is halo, and R⁶ is C₁-C₆ haloalkyl;    -   (xxx) R⁷ is halo, and R⁶ is C₁-C₆ haloalkoxy;    -   (xxxi) R⁷ is C₁-C₆ alkoxy; and R⁶ is halo; or    -   (xxxii) R⁷ is C₁-C₆ alkoxy; and R⁶ is chloro.

In some embodiments, of the compound of formula AA,

the substituted ring B is

and R⁶ and R⁷ are one of the following combinations:

-   -   (i) R⁶ is C₁-C₆ alkyl, and R⁷ is C₁-C₆ alkyl optionally        substituted with one or more halo;    -   (ii) R⁶ is C₁-C₆ alkyl and R⁷ is C₁-C₆ alkyl;    -   (iii) R⁶ is C₁-C₆ alkyl, and R⁷ is C₁-C₆ alkyl substituted with        one or more halo;    -   (iv) R⁶ is C₁-C₆ alkyl, and R⁷ is C₃-C₇ cycloalkyl;    -   (v) R⁶ is C₁-C₆ alkyl, and R⁷ is halo;    -   (vi) R⁶ is C₁-C₆ alkyl, and R⁷ is cyano;    -   (vii) R⁶ is C₃-C₇ cycloalkyl, and R⁷ is C₃-C₇ cycloalkyl;    -   (viii) R⁶ is C₃-C₇ cycloalkyl, and R⁷ is halo;    -   (ix) R⁶ is cyclopropyl and R⁷ is halo;    -   (x) R⁶ is C₁-C₆ alkyl, and R⁷ is C₁-C₆ alkoxy optionally        substituted with one or more halo;    -   (xi) R⁶ is C₁-C₆ alkyl, and R⁷ is C₁-C₆ alkoxy;    -   (xii) R⁶ is C₁-C₆ alkyl, and R⁷ is C₁-C₆ alkoxy substituted with        one or more halo;    -   (xiii) R⁶ is halo, and R⁷ is C₁-C₆ haloalkyl;    -   (xiv) R⁶ is halo, and R⁷ is C₁-C₆ haloalkoxy;    -   (xv) R⁶ is C₁-C₆ alkoxy; and R⁷ is halo;    -   (xvi) R⁶ is C₁-C₆ alkoxy; and R⁷ is chloro;    -   (xvii) R⁷ is C₁-C₆ alkyl, and R⁶ is C₁-C₆ alkyl optionally        substituted with one or more halo;    -   (xviii) R⁷ is C₁-C₆ alkyl, and R⁶ is C₁-C₆ alkyl substituted        with one or more halo;    -   (xix) R⁷ is C₁-C₆ alkyl, and R⁶ is C₃-C₇ cycloalkyl;    -   (xx) R⁷ is C₁-C₆ alkyl, and R⁶ is halo;    -   (xxi) R⁷ is C₁-C₆ alkyl and R⁶ is halo;    -   (xxii) R⁷ is C₁-C₆ alkyl, and R⁶ is cyano;    -   (xxiii) R⁷ is C₃-C₇ cycloalkyl, and R⁶ is C₃-C₇ cycloalkyl;    -   (xxiv) R⁷ is C₃-C₇ cycloalkyl, and R⁶ is halo;    -   (xxv) R⁷ is C₃-C₇ cycloalkyl and R⁶ is halo;    -   (xxvi) R⁷ is C₁-C₆ alkyl, and R⁶ is C₁-C₆ alkoxy optionally        substituted with one or more halo;    -   (xxvii) R⁷ is C₁-C₆ alkyl, and R⁶ is C₁-C₆ alkoxy;    -   (xxviii) R⁷ is C₁-C₆ alkyl, and R⁶ is C₁-C₆ alkoxy substituted        with one or more halo;    -   (xxix) R⁷ is halo, and R⁶ is C₁-C₆ haloalkyl;    -   (xxx) R⁷ is halo, and R⁶ is C₁-C₆ haloalkoxy;    -   (xxxi) R⁷ is C₁-C₆ alkoxy; and R⁶ is halo;    -   (xxxii) R⁷ is C₁-C₆ alkoxy; and R⁶ is chloro;    -   (xxxiii) R⁶ and R⁷ on adjacent atoms taken together with the        atoms connecting them form a C₄-C₆ aliphatic carbocyclic ring        optionally substituted with one or more hydroxy, oxo, or C₁-C₆        alkyl; or    -   (xxxiv) R⁶ and R⁷ on adjacent atoms taken together with the        atoms connecting them form a 5-to-6-membered heterocyclic ring        containing 1 heteroatom independently selected from O, N, and S,        wherein the heterocyclic ring optionally substituted with one or        more hydroxy, oxo, or C₁-C₆ alkyl.

In some embodiments, of the compound of formula AA,

the substituted ring B is

and R⁶ and R⁷ are one of the following combinations:

-   -   (i) R⁶ is isopropyl; and R⁷ is methyl;    -   (ii) R⁶ is isopropyl; and R⁷ is isopropyl;    -   (iii) R⁶ is isopropyl; and R⁷ is trifluoromethyl;    -   (iv) R⁶ is isopropyl; and R⁷ is cyclopropyl;    -   (v) R⁶ is isopropyl; and R⁷ is chloro;    -   (vi) R⁶ is isopropyl; and R⁷ is fluoro;    -   (vii) R⁶ is ethyl; and R⁷ is fluoro;    -   (viii) R⁶ is isopropyl; and R⁷ is cyano;    -   (ix) R⁶ is cyclopropyl; and R⁷ is cyclopropyl;    -   (x) R⁶ is cyclopropyl; and R⁷ is chloro;    -   (xi) R⁶ is cyclopropyl; and R⁷ is fluoro;    -   (xii) R⁶ is isopropyl; and R⁷ is methoxy;    -   (xiii) R⁶ is isopropyl; and R⁷ is trifluoromethoxy;    -   (xiv) R⁶ is chloro; and R⁷ is trifluoromethyl;    -   (xv) R⁶ is chloro; and R⁷ is trifluoromethoxy;    -   (xvi) R⁷ is isopropyl; and R⁶ is methyl;    -   (xvii) R⁷ is isopropyl; and R⁶ is trifluoromethyl;    -   (xviii) R⁷ is isopropyl; and R⁶ is cyclopropyl;    -   (xix) R⁷ is isopropyl; and R⁶ is chloro;    -   (xx) R⁷ is ethyl; and R⁶ is fluoro;    -   (xxi) R⁷ is isopropyl; and R⁶ is cyano;    -   (xxii) R⁷ is cyclopropyl; and R⁶ is cyclopropyl;    -   (xxiii) R⁷ is cyclopropyl; and R⁶ is chloro;    -   (xxiv) R⁷ is cyclopropyl; and R⁶ is fluoro;    -   (xxv) R⁷ is isopropyl; and R⁶ is methoxy;    -   (xxvi) R⁷ is isopropyl; and R⁶ is trifluoromethoxy;    -   (xxvii) R⁷ is chloro; and R⁶ is trifluoromethyl;    -   (xxviii) R⁷ is chloro; and R⁶ is trifluoromethoxy;    -   (xxix) R⁶ and R⁷ on adjacent atoms taken together with the atoms        connecting them form a C₄ aliphatic carbocyclic ring;    -   (xxx) R⁶ and R⁷ on adjacent atoms taken together with the atoms        connecting them form a C₅ aliphatic carbocyclic ring;    -   (xxxi) R⁶ and R⁷ on adjacent atoms taken together with the atoms        connecting them form a C₆ aliphatic carbocyclic ring;    -   (xxxii) R⁶ and R⁷ on adjacent atoms taken together with the        atoms connecting them form a 5-membered heterocyclic ring        containing 1 heteroatoms independently selected from O, N, and        S;    -   (xxxiii) R⁶ and R⁷ on adjacent atoms taken together with the        atoms connecting them form a 6-membered heterocyclic ring        containing 1 heteroatoms independently selected from O, N, and        S; or    -   (xxxiv) R⁶ and R⁷ on adjacent atoms taken together with the        atoms connecting them form a C₅ aliphatic carbocyclic ring.

In some embodiments, of the compound of formula AA,

the substituted ring B is

and R⁶ and R⁷ are one of the following combinations:

-   -   (i) R⁶ is isopropyl; and R⁷ is methyl;    -   (ii) R⁶ is isopropyl; and R⁷ is isopropyl;    -   (iii) R⁶ is isopropyl; and R⁷ is trifluoromethyl;    -   (iv) R⁶ is isopropyl; and R⁷ is cyclopropyl;    -   (v) R⁶ is isopropyl; and R⁷ is chloro;    -   (vi) R⁶ is isopropyl; and R⁷ is fluoro;    -   (vii) R⁶ is ethyl; and R⁷ is fluoro;    -   (viii) R⁶ is isopropyl; and R⁷ is cyano;    -   (ix) R⁶ is cyclopropyl; and R⁷ is cyclopropyl;    -   (x) R⁶ is cyclopropyl; and R⁷ is chloro;    -   (xi) R⁶ is cyclopropyl; and R⁷ is fluoro;    -   (xii) R⁶ is isopropyl; and R⁷ is methoxy;    -   (xiii) R⁶ is isopropyl; and R⁷ is trifluoromethoxy;    -   (xiv) R⁶ is chloro; and R⁷ is trifluoromethyl;    -   (xv) R⁶ is chloro; and R⁷ is trifluoromethoxy;    -   (xvi) R⁷ is isopropyl; and R⁶ is methyl;    -   (xvii) R⁷ is isopropyl; and R⁶ is trifluoromethyl;    -   (xviii) R⁷ is isopropyl; and R⁶ is cyclopropyl;    -   (xix) R⁷ is isopropyl; and R⁶ is chloro;    -   (xx) R⁷ is ethyl; and R⁶ is fluoro;    -   (xxi) R⁷ is isopropyl; and R⁶ is cyano;    -   (xxii) R⁷ is cyclopropyl; and R⁶ is cyclopropyl;    -   (xxiii) R⁷ is cyclopropyl; and R⁶ is chloro;    -   (xxiv) R⁷ is cyclopropyl; and R⁶ is fluoro;    -   (xxv) R⁷ is isopropyl; and R⁶ is methoxy;    -   (xxvi) R⁷ is isopropyl; and R⁶ is trifluoromethoxy;    -   (xxvii) R⁷ is chloro; and R⁶ is trifluoromethyl; or    -   (xxviii) R⁷ is chloro; and R⁶ is trifluoromethoxy.

In some embodiments, of the compound of formula AA,

the substituted ring B is

and R⁶ and R⁷ are one of the following combinations:

-   -   (i) each R⁶ is independently C₁-C₆ alkyl, and R⁷ is C₁-C₆ alkyl        optionally substituted with one or more halo;    -   (ii) each R⁶ is independently C₁-C₆ alkyl and R⁷ is C₁-C₆ alkyl;    -   (iii) each R⁶ is independently C₁-C₆ alkyl, and R⁷ is C₁-C₆        alkyl substituted with one or more halo;    -   (iv) each R⁶ is independently C₁-C₆ alkyl, and R⁷ is C₃-C₇        cycloalkyl;    -   (v) each R⁶ is independently C₁-C₆ alkyl, and R⁷ is halo;    -   (vi) each R⁶ is independently C₁-C₆ alkyl, and R⁷ is cyano;    -   (vii) each R⁶ is independently C₃-C₇ cycloalkyl, and R⁷ is C₃-C₇        cycloalkyl;    -   (viii) each R⁶ is independently C₃-C₇ cycloalkyl, and R⁷ is        halo;    -   (ix) each R⁶ is independently cyclopropyl and R⁷ is halo;    -   (x) each R⁶ is independently C₁-C₆ alkyl, and R⁷ is C₁-C₆ alkoxy        optionally substituted with one or more halo;    -   (xi) each R⁶ is independently C₁-C₆ alkyl, and R⁷ is C₁-C₆        alkoxy;    -   (xii) each R⁶ is independently C₁-C₆ alkyl, and R⁷ is C₁-C₆        alkoxy substituted with one or more halo;    -   (xiii) each R⁶ is independently halo, and R⁷ is C₁-C₆ haloalkyl;    -   (xiv) each R⁶ is independently halo, and R⁷ is C₁-C₆ haloalkoxy;    -   (xv) each R⁶ is independently C₁-C₆ alkoxy; and R⁷ is halo;    -   (xvi) each R⁶ is independently C₁-C₆ alkoxy; and R⁷ is chloro;    -   (xvii) R⁷ is C₁-C₆ alkyl, and each R⁶ is independently C₁-C₆        alkyl optionally substituted with one or more halo;    -   (xviii) R⁷ is C₁-C₆ alkyl, and each R⁶ is independently C₁-C₆        alkyl substituted with one or more halo;    -   (xix) R⁷ is C₁-C₆ alkyl, and each R⁶ is independently C₃-C₇        cycloalkyl;    -   (xx) R⁷ is C₁-C₆ alkyl, and each R⁶ is independently halo;    -   (xxi) R⁷ is C₁-C₆ alkyl and each R⁶ is independently halo;    -   (xxii) R⁷ is C₁-C₆ alkyl, and R⁶ is cyano;    -   (xxiii) R⁷ is C₃-C₇ cycloalkyl, and each R⁶ is independently        C₃-C₇ cycloalkyl;    -   (xxiv) R⁷ is C₃-C₇ cycloalkyl, and each R⁶ is independently        halo;    -   (xxv) R⁷ is C₃-C₇ cycloalkyl and each R⁶ is independently halo;    -   (xxvi) R⁷ is C₁-C₆ alkyl, and each R⁶ is independently C₁-C₆        alkoxy optionally substituted with one or more halo;    -   (xxvii) R⁷ is C₁-C₆ alkyl, and each R⁶ is independently C₁-C₆        alkoxy;    -   (xxviii) R⁷ is C₁-C₆ alkyl, and each R⁶ is independently C₁-C₆        alkoxy substituted with one or more halo;    -   (xxix) R⁷ is halo, and each R⁶ is independently C₁-C₆ haloalkyl;    -   (xxx) R⁷ is halo, and each R⁶ is independently C₁-C₆ haloalkoxy;    -   (xxxi) R⁷ is C₁-C₆ alkoxy; and each R⁶ is independently halo;    -   (xxxii) R⁷ is C₁-C₆ alkoxy; and R⁶ is chloro;    -   (xxxiii) R⁶ and R⁷ on adjacent atoms taken together with the        atoms connecting them form a C₅ aliphatic carbocyclic ring;    -   (xxxiv) R⁶ and R⁷ on adjacent atoms taken together with the        atoms connecting them form a C₄-C₆ aliphatic carbocyclic ring        optionally substituted with one or more hydroxy, oxo, or C₁-C₆        alkyl; and one R⁶ is halo or cyano; or    -   (xxxv) R⁶ and R⁷ on adjacent atoms taken together with the atoms        connecting them form a 5-to-6-membered heterocyclic ring        containing 1 heteroatom independently selected from O, N, and S,        wherein the heterocyclic ring optionally substituted with one or        more hydroxy, oxo, or C₁-C₆ alkyl; and one R⁶ is halo or cyano.

In some embodiments, of the compound of formula AA,

the substituted ring B is

and R⁶ and R⁷ are one of the following combinations:

-   -   (i) each R⁶ is isopropyl; and R⁷ is methyl;    -   (ii) each R⁶ is isopropyl; and R⁷ is isopropyl;    -   (iii) each R⁶ is isopropyl; and R⁷ is trifluoromethyl;    -   (iv) each R⁶ is isopropyl; and R⁷ is cyclopropyl;    -   (v) each R⁶ is isopropyl; and R⁷ is chloro;    -   (vi) each R⁶ is isopropyl; and R⁷ is fluoro;    -   (vii) each R⁶ is ethyl; and R⁷ is fluoro;    -   (viii) each R⁶ is isopropyl; and R⁷ is cyano;    -   (ix) each R⁶ is cyclopropyl; and R⁷ is cyclopropyl;    -   (x) each R⁶ is cyclopropyl; and R⁷ is chloro;    -   (xi) each R⁶ is cyclopropyl; and R⁷ is fluoro;    -   (xii) each R⁶ is isopropyl; and R⁷ is methoxy;    -   (xiii) each R⁶ is isopropyl; and R⁷ is trifluoromethoxy;    -   (xiv) each R⁶ is chloro; and R⁷ is trifluoromethyl;    -   (xv) each R⁶ is chloro; and R⁷ is trifluoromethoxy;    -   (xvi) R⁷ is isopropyl; and each R⁶ is methyl;    -   (xvii) R⁷ is isopropyl; and each R⁶ is trifluoromethyl;    -   (xviii) R⁷ is isopropyl; and each R⁶ is cyclopropyl;    -   (xix) R⁷ is isopropyl; and each R⁶ is chloro;    -   (xx) R⁷ is ethyl; and each R⁶ is fluoro;    -   (xxi) R⁷ is isopropyl; and each R⁶ is cyano;    -   (xxii) R⁷ is cyclopropyl; and each R⁶ is cyclopropyl;    -   (xxiii) R⁷ is cyclopropyl; and each R⁶ is chloro;    -   (xxiv) R⁷ is cyclopropyl; and each R⁶ is fluoro;    -   (xxv) R⁷ is isopropyl; and each R⁶ is methoxy;    -   (xxvi) R⁷ is isopropyl; and each R⁶ is trifluoromethoxy;    -   (xxvii) R⁷ is chloro; and each R⁶ is trifluoromethyl;    -   (xxviii) R⁷ is chloro; and each R⁶ is trifluoromethoxy;    -   (xxix) one R⁶ is isopropyl; the other R⁶ is trifluoromethyl; and        R⁷ is chloro;    -   (xxx) R⁶ and R⁷ on adjacent atoms taken together with the atoms        connecting them form a C₄ aliphatic carbocyclic ring; and one R⁶        is fluoro, chloro, or cyano;    -   (xxxi) R⁶ and R⁷ on adjacent atoms taken together with the atoms        connecting them form a C₅ aliphatic carbocyclic ring; and one R⁶        is fluoro, chloro, or cyano;    -   (xxxii) R⁶ and R⁷ on adjacent atoms taken together with the        atoms connecting them form a C₆ aliphatic carbocyclic ring; and        one R⁶ is fluoro, chloro, or cyano;    -   (xxxiii) R⁶ and R⁷ on adjacent atoms taken together with the        atoms connecting them form a 5-membered heterocyclic ring        containing 1 heteroatoms independently selected from 0, N, and        S; and one R⁶ is fluoro, chloro, or cyano; or    -   (xxxiv) R⁶ and R⁷ on adjacent atoms taken together with the        atoms connecting them form a 6-membered heterocyclic ring        containing 1 heteroatoms independently selected from 0, N, and        S; and one R⁶ is fluoro, chloro, or cyano.

In some embodiments, of the compound of formula AA,

the substituted ring B is

and R⁶ and R⁷ are one of the following combinations:

-   -   (i) each R⁶ is independently C₁-C₆ alkyl, and R⁷ is C₁-C₆ alkyl        optionally substituted with one or more halo;    -   (ii) each R⁶ is independently C₁-C₆ alkyl and R⁷ is C₁-C₆ alkyl;    -   (iii) each R⁶ is independently C₁-C₆ alkyl, and R⁷ is C₁-C₆        alkyl substituted with one or more halo;    -   (iv) each R⁶ is independently C₁-C₆ alkyl, and R⁷ is C₃-C₇        cycloalkyl;    -   (v) each R⁶ is independently C₁-C₆ alkyl, and R⁷ is halo;    -   (vi) each R⁶ is independently C₁-C₆ alkyl, and R⁷ is cyano;    -   (vii) each R⁶ is independently C₃-C₇ cycloalkyl, and R⁷ is C₃-C₇        cycloalkyl;    -   (viii) each R⁶ is independently C₃-C₇ cycloalkyl, and R⁷ is        halo;    -   (ix) each R⁶ is independently cyclopropyl and R⁷ is halo;    -   (x) each R⁶ is independently C₁-C₆ alkyl, and R⁷ is C₁-C₆ alkoxy        optionally substituted with one or more halo;    -   (xi) each R⁶ is independently C₁-C₆ alkyl, and R⁷ is C₁-C₆        alkoxy;    -   (xii) each R⁶ is independently C₁-C₆ alkyl, and R⁷ is C₁-C₆        alkoxy substituted with one or more halo;    -   (xiii) each R⁶ is independently halo, and R⁷ is C₁-C₆ haloalkyl;    -   (xiv) each R⁶ is independently halo, and R⁷ is C₁-C₆ haloalkoxy;    -   (xv) each R⁶ is independently C₁-C₆ alkoxy; and R⁷ is halo;    -   (xvi) each R⁶ is independently C₁-C₆ alkoxy; and R⁷ is chloro;    -   (xvii) R⁷ is C₁-C₆ alkyl, and each R⁶ is independently C₁-C₆        alkyl optionally substituted with one or more halo;    -   (xviii) R⁷ is C₁-C₆ alkyl, and each R⁶ is independently C₁-C₆        alkyl substituted with one or more halo;    -   (xix) R⁷ is C₁-C₆ alkyl, and each R⁶ is independently C₃-C₇        cycloalkyl;    -   (xx) R⁷ is C₁-C₆ alkyl, and each R⁶ is independently halo;    -   (xxi) R⁷ is C₁-C₆ alkyl and each R⁶ is independently halo;    -   (xxii) R⁷ is C₁-C₆ alkyl, and R⁶ is cyano;    -   (xxiii) R⁷ is C₃-C₇ cycloalkyl, and each R⁶ is independently        C₃-C₇ cycloalkyl;    -   (xxiv) R⁷ is C₃-C₇ cycloalkyl, and each R⁶ is independently        halo;    -   (xxv) R⁷ is C₃-C₇ cycloalkyl and each R⁶ is independently halo;    -   (xxvi) R⁷ is C₁-C₆ alkyl, and each R⁶ is independently C₁-C₆        alkoxy optionally substituted with one or more halo;    -   (xxvii) R⁷ is C₁-C₆ alkyl, and each R⁶ is independently C₁-C₆        alkoxy;    -   (xxviii) R⁷ is C₁-C₆ alkyl, and each R⁶ is independently C₁-C₆        alkoxy substituted with one or more halo;    -   (xxix) R⁷ is halo, and each R⁶ is independently C₁-C₆ haloalkyl;    -   (xxx) R⁷ is halo, and each R⁶ is independently C₁-C₆ haloalkoxy;    -   (xxxi) R⁷ is C₁-C₆ alkoxy; and each R⁶ is independently halo; or    -   (xxxii) R⁷ is C₁-C₆ alkoxy; and R⁶ is chloro.

In some embodiments, of the compound of formula AA,

the substituted ring B is

and R⁶ and R⁷ are one of the following combinations:

-   -   (i) each R⁶ is isopropyl; and R⁷ is methyl;    -   (ii) each R⁶ is isopropyl; and R⁷ is isopropyl;    -   (iii) each R⁶ is isopropyl; and R⁷ is trifluoromethyl;    -   (iv) each R⁶ is isopropyl; and R⁷ is cyclopropyl;    -   (v) each R⁶ is isopropyl; and R⁷ is chloro;    -   (vi) each R⁶ is isopropyl; and R⁷ is fluoro;    -   (vii) each R⁶ is ethyl; and R⁷ is fluoro;    -   (viii) each R⁶ is isopropyl; and R⁷ is cyano;    -   (ix) each R⁶ is cyclopropyl; and R⁷ is cyclopropyl;    -   (x) each R⁶ is cyclopropyl; and R⁷ is chloro;    -   (xi) each R⁶ is cyclopropyl; and R⁷ is fluoro;    -   (xii) each R⁶ is isopropyl; and R⁷ is methoxy;    -   (xiii) each R⁶ is isopropyl; and R⁷ is trifluoromethoxy;    -   (xiv) each R⁶ is chloro; and R⁷ is trifluoromethyl;    -   (xv) each R⁶ is chloro; and R⁷ is trifluoromethoxy;    -   (xvi) R⁷ is isopropyl; and each R⁶ is methyl;    -   (xvii) R⁷ is isopropyl; and each R⁶ is trifluoromethyl;    -   (xviii) R⁷ is isopropyl; and each R⁶ is cyclopropyl;    -   (xix) R⁷ is isopropyl; and each R⁶ is chloro;    -   (xx) R⁷ is ethyl; and each R⁶ is fluoro;    -   (xxi) R⁷ is isopropyl; and each R⁶ is cyano;    -   (xxii) R⁷ is cyclopropyl; and each R⁶ is cyclopropyl;    -   (xxiii) R⁷ is cyclopropyl; and each R⁶ is chloro;    -   (xxiv) R⁷ is cyclopropyl; and each R⁶ is fluoro;    -   (xxv) R⁷ is isopropyl; and each R⁶ is methoxy;    -   (xxvi) R⁷ is isopropyl; and each R⁶ is trifluoromethoxy;    -   (xxvii) R⁷ is chloro; and each R⁶ is trifluoromethyl;    -   (xxviii) R⁷ is chloro; and each R⁶ is trifluoromethoxy; or    -   (xxix) one R⁶ is isopropyl; the other R⁶ is trifluoromethyl; and        R⁷ is chloro.

In some embodiments, of the compound of formula AA,

the substituted ring B is

and R⁶ and R⁷ are one of the following combinations:

-   -   (i) R⁶ is C₁-C₆ alkyl, and each R⁷ is independently C₁-C₆ alkyl        optionally substituted with one or more halo;    -   (ii) R⁶ is C₁-C₆ alkyl and each R⁷ is independently C₁-C₆ alkyl;    -   (iii) R⁶ is C₁-C₆ alkyl, and each R⁷ is independently C₁-C₆        alkyl substituted with one or more halo;    -   (iv) R⁶ is C₁-C₆ alkyl, and each R⁷ is independently C₃-C₇        cycloalkyl;    -   (v) R⁶ is C₁-C₆ alkyl, and each R⁷ is independently halo;    -   (vi) R⁶ is C₁-C₆ alkyl, and R⁷ is cyano;    -   (vii) R⁶ is C₃-C₇ cycloalkyl, and each R⁷ is independently C₃-C₇        cycloalkyl;    -   (viii) R⁶ is C₃-C₇ cycloalkyl, and each R⁷ is independently        halo;    -   (ix) R⁶ is cyclopropyl and each R⁷ is independently halo;    -   (x) R⁶ is C₁-C₆ alkyl, and each R⁷ is independently C₁-C₆ alkoxy        optionally substituted with one or more halo;    -   (xi) R⁶ is C₁-C₆ alkyl, and each R⁷ is independently C₁-C₆        alkoxy;    -   (xii) R⁶ is C₁-C₆ alkyl, and each R⁷ is independently C₁-C₆        alkoxy substituted with one or more halo;    -   (xiii) R⁶ is halo, and each R⁷ is independently C₁-C₆ haloalkyl;    -   (xiv) R⁶ is halo, and each R⁷ is independently C₁-C₆ haloalkoxy;    -   (xv) R⁶ is C₁-C₆ alkoxy; and each R⁷ is independently halo;    -   (xvi) R⁶ is C₁-C₆ alkoxy; and R⁷ is chloro;    -   (xvii) each R⁷ is independently C₁-C₆ alkyl, and R⁶ is C₁-C₆        alkyl optionally substituted with one or more halo;    -   (xviii) each R⁷ is independently C₁-C₆ alkyl, and R⁶ is C₁-C₆        alkyl substituted with one or more halo;    -   (xix) each R⁷ is independently C₁-C₆ alkyl, and R⁶ is C₃-C₇        cycloalkyl;    -   (xx) each R⁷ is independently C₁-C₆ alkyl, and R⁶ is halo;    -   (xxi) each R⁷ is independently C₁-C₆ alkyl and R⁶ is halo;    -   (xxii) each R⁷ is independently C₁-C₆ alkyl, and R⁶ is cyano;    -   (xxiii) each R⁷ is independently C₃-C₇ cycloalkyl, and R⁶ is        C₃-C₇ cycloalkyl.    -   (xxiv) each R⁷ is independently C₃-C₇ cycloalkyl, and R⁶ is        halo;    -   (xxv) each R⁷ is independently C₃-C₇ cycloalkyl and R⁶ is halo;    -   (xxvi) each R⁷ is independently C₁-C₆ alkyl, and R⁶ is C₁-C₆        alkoxy optionally substituted with one or more halo;    -   (xxvii) each R⁷ is independently C₁-C₆ alkyl, and R⁶ is C₁-C₆        alkoxy;    -   (xxviii) each R⁷ is independently C₁-C₆ alkyl, and R⁶ is C₁-C₆        alkoxy substituted with one or more halo;    -   (xxix) each R⁷ is independently halo, and R⁶ is C₁-C₆ haloalkyl;    -   (xxx) each R⁷ is independently halo, and R⁶ is C₁-C₆ haloalkoxy;    -   (xxxi) each R⁷ is independently C₁-C₆ alkoxy; and R⁶ is halo;    -   (xxxii) each R⁷ is independently C₁-C₆ alkoxy; and R⁶ is chloro;    -   (xxxiii) R⁶ and R⁷ on adjacent atoms taken together with the        atoms connecting them form a C₅ aliphatic carbocyclic ring;    -   (xxxiv) R⁶ and R⁷ on adjacent atoms taken together with the        atoms connecting them form a C₄-C₆ aliphatic carbocyclic ring        optionally substituted with one or more hydroxy, oxo, or C₁-C₆        alkyl; or    -   (xxxv) R⁶ and R⁷ on adjacent atoms taken together with the atoms        connecting them form a 5-to-6-membered heterocyclic ring        containing 1 heteroatom independently selected from O, N, and S,        wherein the heterocyclic ring optionally substituted with one or        more hydroxy, oxo, or C₁-C₆ alkyl.

In some embodiments, of the compound of formula AA,

the substituted ring B is

and R⁶ and R⁷ are one of the following combinations:

-   -   (i) R⁶ is isopropyl; and each R⁷ is methyl;    -   (ii) R⁶ is isopropyl; and each R⁷ is isopropyl;    -   (iii) R⁶ is isopropyl; and each R⁷ is trifluoromethyl;    -   (iv) R⁶ is isopropyl; and each R⁷ is cyclopropyl;    -   (v) R⁶ is isopropyl; and each R⁷ is chloro;    -   (vi) R⁶ is isopropyl; and each R⁷ is fluoro;    -   (vii) R⁶ is ethyl; and each R⁷ is fluoro;    -   (viii) R⁶ is isopropyl; and each R⁷ is cyano;    -   (ix) R⁶ is cyclopropyl; and each R⁷ is cyclopropyl;    -   (x) R⁶ is cyclopropyl; and each R⁷ is chloro;    -   (xi) R⁶ is cyclopropyl; and each R⁷ is fluoro;    -   (xii) R⁶ is isopropyl; and R⁷ is methoxy;    -   (xiii) R⁶ is isopropyl; and each R⁷ is trifluoromethoxy;    -   (xiv) R⁶ is chloro; and each R⁷ is trifluoromethyl;    -   (xv) R⁶ is chloro; and each R⁷ is trifluoromethoxy;    -   (xvi) each R⁷ is isopropyl; and R⁶ is methyl;    -   (xvii) each R⁷ is isopropyl; and R⁶ is trifluoromethyl;    -   (xviii) each R⁷ is isopropyl; and R⁶ is cyclopropyl;    -   (xix) each R⁷ is isopropyl; and R⁶ is chloro;    -   (xx) each R⁷ is ethyl; and R⁶ is fluoro;    -   (xxi) each R⁷ is isopropyl; and R⁶ is cyano;    -   (xxii) each R⁷ is cyclopropyl; and R⁶ is cyclopropyl;    -   (xxiii) each R⁷ is cyclopropyl; and R⁶ is chloro;    -   (xxiv) each R⁷ is cyclopropyl; and R⁶ is fluoro;    -   (xxv) each R⁷ is isopropyl; and R⁶ is methoxy;    -   (xxvi) each R⁷ is isopropyl; and R⁶ is trifluoromethoxy;    -   (xxvii) each R⁷ is chloro; and R⁶ is trifluoromethyl;    -   (xxviii) each R⁷ is chloro; and R⁶ is trifluoromethoxy;    -   (xxix) R⁶ and R⁷ on adjacent atoms taken together with the atoms        connecting them form a C₅ aliphatic carbocyclic ring; and one R⁷        is fluoro, chloro, or cyano;    -   (xxx) R⁶ and R⁷ on adjacent atoms taken together with the atoms        connecting them form a C₄ aliphatic carbocyclic ring; and one R⁷        is fluoro, chloro, or cyano;    -   (xxxi) R⁶ and R⁷ on adjacent atoms taken together with the atoms        connecting them form a C₆ aliphatic carbocyclic ring; and one R⁷        is fluoro, chloro, or cyano;    -   (xxxii) R⁶ and R⁷ on adjacent atoms taken together with the        atoms connecting them form a 5-membered heterocyclic ring        containing 1 heteroatoms independently selected from 0, N, and        S; and one R⁷ is fluoro, chloro, or cyano; or    -   (xxxiii) R⁶ and R⁷ on adjacent atoms taken together with the        atoms connecting them form a 6-membered heterocyclic ring        containing 1 heteroatoms independently selected from 0, N, and        S; and one R⁷ is fluoro, chloro, or cyano.

In some embodiments, of the compound of formula AA,

the substituted ring B is

and R⁶ and R⁷ are one of the following combinations:

-   -   (i) R⁶ is C₁-C₆ alkyl, and each R⁷ is independently C₁-C₆ alkyl        optionally substituted with one or more halo;    -   (ii) R⁶ is C₁-C₆ alkyl and each R⁷ is independently C₁-C₆ alkyl;    -   (iii) R⁶ is C₁-C₆ alkyl, and each R⁷ is independently C₁-C₆        alkyl substituted with one or more halo;    -   (iv) R⁶ is C₁-C₆ alkyl, and each R⁷ is independently C₃-C₇        cycloalkyl;    -   (v) R⁶ is C₁-C₆ alkyl, and each R⁷ is independently halo;    -   (vi) R⁶ is C₁-C₆ alkyl, and R⁷ is cyano;    -   (vii) R⁶ is C₃-C₇ cycloalkyl, and each R⁷ is independently C₃-C₇        cycloalkyl;    -   (viii) R⁶ is C₃-C₇ cycloalkyl, and each R⁷ is independently        halo;    -   (ix) R⁶ is cyclopropyl and each R⁷ is independently halo;    -   (x) R⁶ is C₁-C₆ alkyl, and each R⁷ is independently C₁-C₆ alkoxy        optionally substituted with one or more halo;    -   (xi) R⁶ is C₁-C₆ alkyl, and each R⁷ is independently C₁-C₆        alkoxy;    -   (xii) R⁶ is C₁-C₆ alkyl, and each R⁷ is independently C₁-C₆        alkoxy substituted with one or more halo;    -   (xiii) R⁶ is halo, and each R⁷ is independently C₁-C₆ haloalkyl;    -   (xiv) R⁶ is halo, and each R⁷ is independently C₁-C₆ haloalkoxy;    -   (xv) R⁶ is C₁-C₆ alkoxy; and each R⁷ is independently halo;    -   (xvi) R⁶ is C₁-C₆ alkoxy; and R⁷ is chloro;    -   (xvii) each R⁷ is independently C₁-C₆ alkyl, and R⁶ is C₁-C₆        alkyl optionally substituted with one or more halo;    -   (xviii) each R⁷ is independently C₁-C₆ alkyl, and R⁶ is C₁-C₆        alkyl substituted with one or more halo;    -   (xix) each R⁷ is independently C₁-C₆ alkyl, and R⁶ is C₃-C₇        cycloalkyl;    -   (xx) each R⁷ is independently C₁-C₆ alkyl, and R⁶ is halo;    -   (xxi) each R⁷ is independently C₁-C₆ alkyl and R⁶ is halo;    -   (xxii) each R⁷ is independently C₁-C₆ alkyl, and R⁶ is cyano;    -   (xxiii) each R⁷ is independently C₃-C₇ cycloalkyl, and R⁶ is        C₃-C₇ cycloalkyl;    -   (xxiv) each R⁷ is independently C₃-C₇ cycloalkyl, and R⁶ is        halo;    -   (xxv) each R⁷ is independently C₃-C₇ cycloalkyl and R⁶ is halo;    -   (xxvi) each R⁷ is independently C₁-C₆ alkyl, and R⁶ is C₁-C₆        alkoxy optionally substituted with one or more halo;    -   (xxvii) each R⁷ is independently C₁-C₆ alkyl, and R⁶ is C₁-C₆        alkoxy;    -   (xxviii) each R⁷ is independently C₁-C₆ alkyl, and R⁶ is C₁-C₆        alkoxy substituted with one or more halo;    -   (xxix) each R⁷ is independently halo, and R⁶ is C₁-C₆ haloalkyl;    -   (xxx) each R⁷ is independently halo, and R⁶ is C₁-C₆ haloalkoxy;    -   (xxxi) each R⁷ is independently C₁-C₆ alkoxy; and R⁶ is halo;    -   (xxxii) each R⁶ is independently C₁-C₆ alkoxy; and R⁶ is chloro;    -   (xxxiii) R⁶ and R⁷ on adjacent atoms taken together with the        atoms connecting them form a C₅ aliphatic carbocyclic ring;    -   (xxxiv) R⁶ and R⁷ on adjacent atoms taken together with the        atoms connecting them form a C₄-C₆ aliphatic carbocyclic ring        optionally substituted with one or more hydroxy, oxo, or C₁-C₆        alkyl; or    -   (xxxiv) R⁶ and R⁷ on adjacent atoms taken together with the        atoms connecting them form a 5-to-6-membered heterocyclic ring        containing 1 heteroatom independently selected from O, N, and S,        wherein the heterocyclic ring optionally substituted with one or        more hydroxy, oxo, or C₁-C₆ alkyl.

In some embodiments, of the compound of formula AA,

the substituted ring B is

and R⁶ and R⁷ are one of the following combinations:

-   -   (i) R⁶ is isopropyl; and each R⁷ is methyl;    -   (ii) R⁶ is isopropyl; and each R⁷ is isopropyl;    -   (iii) R⁶ is isopropyl; and each R⁷ is trifluoromethyl;    -   (iv) R⁶ is isopropyl; and each R⁷ is cyclopropyl;    -   (v) R⁶ is isopropyl; and each R⁷ is chloro;    -   (vi) R⁶ is isopropyl; and each R⁷ is fluoro;    -   (vii) R⁶ is ethyl; and each R⁷ is fluoro;    -   (viii) R⁶ is isopropyl; and each R⁷ is cyano;    -   (ix) R⁶ is cyclopropyl; and each R⁷ is cyclopropyl;    -   (x) R⁶ is cyclopropyl; and each R⁷ is chloro;    -   (xi) R⁶ is cyclopropyl; and each R⁷ is fluoro;    -   (xii) R⁶ is isopropyl; and each R⁷ is methoxy;    -   (xiii) R⁶ is isopropyl; and each R⁷ is trifluoromethoxy;    -   (xiv) R⁶ is chloro; and each R⁷ is trifluoromethyl;    -   (xv) R⁶ is chloro; and each R⁷ is trifluoromethoxy;    -   (xvi) each R⁷ is isopropyl; and R⁶ is methyl;    -   (xvii) each R⁷ is isopropyl; and R⁶ is trifluoromethyl;    -   (xviii) each R⁷ is isopropyl; and R⁶ is cyclopropyl;    -   (xix) each R⁷ is isopropyl; and R⁶ is chloro;    -   (xx) each R⁷ is ethyl; and R⁶ is fluoro;    -   (xxi) each R⁷ is isopropyl; and R⁶ is cyano;    -   (xxii) each R⁷ is cyclopropyl; and R⁶ is cyclopropyl;    -   (xxiii) each R⁷ is cyclopropyl; and R⁶ is chloro;    -   (xxiv) each R⁷ is cyclopropyl; and R⁶ is fluoro;    -   (xxv) each R⁷ is isopropyl; and R⁶ is methoxy;    -   (xxvi) each R⁷ is isopropyl; and R⁶ is trifluoromethoxy;    -   (xxvii) each R⁷ is chloro; and R⁶ is trifluoromethyl;    -   (xxviii) each R⁷ is chloro; and R⁶ is trifluoromethoxy;    -   (xxix) R⁶ and R⁷ on adjacent atoms taken together with the atoms        connecting them form a C₅ aliphatic carbocyclic ring; and one R⁷        is fluoro, chloro, or cyano;    -   (xxx) R⁶ and R⁷ on adjacent atoms taken together with the atoms        connecting them form a C₄ aliphatic carbocyclic ring; and one R⁷        is fluoro, chloro, or cyano;    -   (xxxi) R⁶ and R⁷ on adjacent atoms taken together with the atoms        connecting them form a C₆ aliphatic carbocyclic ring; and one R⁷        is fluoro, chloro, or cyano;    -   (xxxii) R⁶ and R⁷ on adjacent atoms taken together with the        atoms connecting them form a 5-membered heterocyclic ring        containing 1 heteroatoms independently selected from 0, N, and        S; and one R⁷ is fluoro, chloro, or cyano; or    -   (xxxiii) R⁶ and R⁷ on adjacent atoms taken together with the        atoms connecting them form a 6-membered heterocyclic ring        containing 1 heteroatoms independently selected from 0, N, and        S; and one R⁷ is fluoro, chloro, or cyano.

In some embodiments, of the compound of formula AA,

the substituted ring B is

and R⁶ and R⁷ are one of the following combinations:

-   -   (i) each R⁶ is independently C₁-C₆ alkyl, and R⁷ is C₁-C₆ alkyl        optionally substituted with one or more halo;    -   (ii) each R⁶ is independently C₁-C₆ alkyl and R⁷ is C₁-C₆ alkyl;    -   (iii) each R⁶ is independently C₁-C₆ alkyl, and R⁷ is C₁-C₆        alkyl substituted with one or more halo;    -   (iv) each R⁶ is independently C₁-C₆ alkyl, and R⁷ is C₃-C₇        cycloalkyl;    -   (v) each R⁶ is independently C₁-C₆ alkyl, and R⁷ is halo;    -   (vi) each R⁶ is independently C₁-C₆ alkyl, and R⁷ is cyano;    -   (vii) each R⁶ is independently C₃-C₇ cycloalkyl, and R⁷ is C₃-C₇        cycloalkyl;    -   (viii) each R⁶ is independently C₃-C₇ cycloalkyl, and R⁷ is        halo;    -   (ix) each R⁶ is independently cyclopropyl and R⁷ is halo;    -   (x) each R⁶ is independently C₁-C₆ alkyl, and R⁷ is C₁-C₆ alkoxy        optionally substituted with one or more halo;    -   (xi) each R⁶ is independently C₁-C₆ alkyl, and R⁷ is C₁-C₆        alkoxy;    -   (xii) each R⁶ is independently C₁-C₆ alkyl, and R⁷ is C₁-C₆        alkoxy substituted with one or more halo;    -   (xiii) each R⁶ is independently halo, and R⁷ is C₁-C₆ haloalkyl;    -   (xiv) each R⁶ is independently halo, and R⁷ is C₁-C₆ haloalkoxy;    -   (xv) each R⁶ is independently C₁-C₆ alkoxy; and R⁷ is halo;    -   (xvi) each R⁶ is independently C₁-C₆ alkoxy; and R⁷ is chloro;    -   (xvii) R⁷ is C₁-C₆ alkyl, and each R⁶ is independently C₁-C₆        alkyl optionally substituted with one or more halo;    -   (xviii) R⁷ is C₁-C₆ alkyl, and each R⁶ is independently C₁-C₆        alkyl substituted with one or more halo;    -   (xix) R⁷ is C₁-C₆ alkyl, and each R⁶ is independently C₃-C₇        cycloalkyl;    -   (xx) R⁷ is C₁-C₆ alkyl, and each R⁶ is independently halo;    -   (xxi) R⁷ is C₁-C₆ alkyl and each R⁶ is independently halo;    -   (xxii) R⁷ is C₁-C₆ alkyl, and R⁶ is cyano;    -   (xxiii) R⁷ is C₃-C₇ cycloalkyl, and each R⁶ is independently        C₃-C₇ cycloalkyl;    -   (xxiv) R⁷ is C₃-C₇ cycloalkyl, and each R⁶ is independently        halo;    -   (xxv) R⁷ is C₃-C₇ cycloalkyl and each R⁶ is independently halo;    -   (xxvi) R⁷ is C₁-C₆ alkyl, and each R⁶ is independently C₁-C₆        alkoxy optionally substituted with one or more halo;    -   (xxvii) R⁷ is C₁-C₆ alkyl, and each R⁶ is independently C₁-C₆        alkoxy;    -   (xxviii) R⁷ is C₁-C₆ alkyl, and each R⁶ is independently C₁-C₆        alkoxy substituted with one or more halo;    -   (xxix) R⁷ is halo, and each R⁶ is independently C₁-C₆ haloalkyl;    -   (xxx) R⁷ is halo, and each R⁶ is independently C₁-C₆ haloalkoxy;    -   (xxxi) R⁷ is C₁-C₆ alkoxy; and each R⁶ is independently halo; or    -   (xxxii) R⁷ is C₁-C₆ alkoxy; and R⁶ is chloro.

In some embodiments, of the compound of formula AA,

the substituted ring B is

and R⁶ and R⁷ are one of the following combinations:

-   -   (i) each R⁶ is isopropyl; and R⁷ is methyl;    -   (ii) each R⁶ is isopropyl; and R⁷ is isopropyl;    -   (iii) each R⁶ is isopropyl; and R⁷ is trifluoromethyl;    -   (iv) each R⁶ is isopropyl; and R⁷ is cyclopropyl;    -   (v) each R⁶ is isopropyl; and R⁷ is chloro;    -   (vi) each R⁶ is isopropyl; and R⁷ is fluoro;    -   (vii) each R⁶ is ethyl; and R⁷ is fluoro;    -   (viii) each R⁶ is isopropyl; and R⁷ is cyano;    -   (ix) each R⁶ is cyclopropyl; and R⁷ is cyclopropyl;    -   (x) each R⁶ is cyclopropyl; and R⁷ is chloro;    -   (xi) each R⁶ is cyclopropyl; and R⁷ is fluoro;    -   (xii) each R⁶ is isopropyl; and R⁷ is methoxy;    -   (xiii) each R⁶ is isopropyl; and R⁷ is trifluoromethoxy;    -   (xiv) each R⁶ is chloro; and R⁷ is trifluoromethyl;    -   (xv) each R⁶ is chloro; and R⁷ is trifluoromethoxy;    -   (xvi) R⁷ is isopropyl; and each R⁶ is methyl;    -   (xvii) R⁷ is isopropyl; and each R⁶ is trifluoromethyl;    -   (xviii) R⁷ is isopropyl; and each R⁶ is cyclopropyl;    -   (xix) R⁷ is isopropyl; and each R⁶ is chloro;    -   (xx) R⁷ is ethyl; and each R⁶ is fluoro;    -   (xxi) R⁷ is isopropyl; and each R⁶ is cyano;    -   (xxii) R⁷ is cyclopropyl; and each R⁶ is cyclopropyl;    -   (xxiii) R⁷ is cyclopropyl; and each R⁶ is chloro;    -   (xxiv) R⁷ is cyclopropyl; and each R⁶ is fluoro;    -   (xxv) R⁷ is isopropyl; and each R⁶ is methoxy;    -   (xxvi) R⁷ is isopropyl; and each R⁶ is trifluoromethoxy;    -   (xxvii) R⁷ is chloro; and each R⁶ is trifluoromethyl;    -   (xxviii) R⁷ is chloro; and each R⁶ is trifluoromethoxy; or    -   (xxix) one R⁶ is isopropyl; the other R⁶ is trifluoromethyl; and        R⁷ is chloro.

In some embodiments, of the compound of formula AA,

the substituted ring B is

and R⁶ and R⁷ are one of the following combinations:

-   -   (i) R⁶ is C₁-C₆ alkyl, and each R⁷ is independently C₁-C₆ alkyl        optionally substituted with one or more halo;    -   (ii) R⁶ is C₁-C₆ alkyl and each R⁷ is independently C₁-C₆ alkyl;    -   (iii) R⁶ is C₁-C₆ alkyl, and each R⁷ is independently C₁-C₆        alkyl substituted with one or more halo;    -   (iv) R⁶ is C₁-C₆ alkyl, and each R⁷ is independently C₃-C₇        cycloalkyl;    -   (v) R⁶ is C₁-C₆ alkyl, and each R⁷ is independently halo;    -   (vi) R⁶ is C₁-C₆ alkyl, and R⁷ is cyano;    -   (vii) R⁶ is C₃-C₇ cycloalkyl, and each R⁷ is independently C₃-C₇        cycloalkyl;    -   (viii) R⁶ is C₃-C₇ cycloalkyl, and each R⁷ is independently        halo;    -   (ix) R⁶ is cyclopropyl and each R⁷ is independently halo;    -   (x) R⁶ is C₁-C₆ alkyl, and each R⁷ is independently C₁-C₆ alkoxy        optionally substituted with one or more halo;    -   (xi) R⁶ is C₁-C₆ alkyl, and each R⁷ is independently C₁-C₆        alkoxy;    -   (xii) R⁶ is C₁-C₆ alkyl, and each R⁷ is independently C₁-C₆        alkoxy substituted with one or more halo;    -   (xiii) R⁶ is halo, and each R⁷ is independently C₁-C₆ haloalkyl;    -   (xiv) R⁶ is halo, and each R⁷ is independently C₁-C₆ haloalkoxy;    -   (xv) R⁶ is C₁-C₆ alkoxy; and each R⁷ is independently halo;    -   (xvi) R⁶ is C₁-C₆ alkoxy; and R⁷ is chloro;    -   (xvii) each R⁷ is independently C₁-C₆ alkyl, and R⁶ is C₁-C₆        alkyl optionally substituted with one or more halo;    -   (xviii) each R⁷ is independently C₁-C₆ alkyl, and R⁶ is C₁-C₆        alkyl substituted with one or more halo;    -   (xix) each R⁷ is independently C₁-C₆ alkyl, and R⁶ is C₃-C₇        cycloalkyl;    -   (xx) each R⁷ is independently C₁-C₆ alkyl, and R⁶ is halo;    -   (xxi) each R⁷ is independently C₁-C₆ alkyl and R⁶ is halo;    -   (xxii) each R⁷ is independently C₁-C₆ alkyl, and R⁶ is cyano;    -   (xxiii) each R⁷ is independently C₃-C₇ cycloalkyl, and R⁶ is        C₃-C₇ cycloalkyl;    -   (xxiv) each R⁷ is independently C₃-C₇ cycloalkyl, and R⁶ is        halo;    -   (xxv) each R⁷ is independently C₃-C₇ cycloalkyl and R⁶ is halo;    -   (xxvi) each R⁷ is independently C₁-C₆ alkyl, and R⁶ is C₁-C₆        alkoxy optionally substituted with one or more halo;    -   (xxvii) each R⁷ is independently C₁-C₆ alkyl, and R⁶ is C₁-C₆        alkoxy;    -   (xxviii) each R⁷ is independently C₁-C₆ alkyl, and R⁶ is C₁-C₆        alkoxy substituted with one or more halo;    -   (xxix) each R⁷ is independently halo, and R⁶ is C₁-C₆ haloalkyl;    -   (xxx) each R⁷ is independently halo, and R⁶ is C₁-C₆ haloalkoxy;    -   (xxxi) each R⁷ is independently C₁-C₆ alkoxy; and R⁶ is halo; or    -   (xxxii) each R⁷ is independently C₁-C₆ alkoxy; and R⁶ is chloro.

In some embodiments, of the compound of formula AA,

the substituted ring B is

and R⁶ and R⁷ are one of the following combinations:

-   -   (i) R⁶ is isopropyl; and each R⁷ is methyl;    -   (ii) R⁶ is isopropyl; and each R⁷ is isopropyl;    -   (iii) R⁶ is isopropyl; and each R⁷ is trifluoromethyl;    -   (iv) R⁶ is isopropyl; and each R⁷ is cyclopropyl;    -   (v) R⁶ is isopropyl; and each R⁷ is chloro;    -   (vi) R⁶ is isopropyl; and each R⁷ is fluoro;    -   (vii) R⁶ is ethyl; and each R⁷ is fluoro;    -   (viii) R⁶ is isopropyl; and each R⁷ is cyano;    -   (ix) R⁶ is cyclopropyl; and each R⁷ is cyclopropyl;    -   (x) R⁶ is cyclopropyl; and each R⁷ is chloro;    -   (xi) R⁶ is cyclopropyl; and each R⁷ is fluoro;    -   (xii) R⁶ is isopropyl; and each R⁷ is methoxy;    -   (xiii) R⁶ is isopropyl; and each R⁷ is trifluoromethoxy;    -   (xiv) R⁶ is chloro; and each R⁷ is trifluoromethyl;    -   (xv) R⁶ is chloro; and each R⁷ is trifluoromethoxy;    -   (xvi) each R⁷ is isopropyl; and R⁶ is methyl;    -   (xvii) each R⁷ is isopropyl; and R⁶ is trifluoromethyl;    -   (xviii) each R⁷ is isopropyl; and R⁶ is cyclopropyl;    -   (xix) each R⁷ is isopropyl; and R⁶ is chloro;    -   (xx) each R⁷ is ethyl; and R⁶ is fluoro;    -   (xxi) each R⁷ is isopropyl; and R⁶ is cyano;    -   (xxii) each R⁷ is cyclopropyl; and R⁶ is cyclopropyl;    -   (xxiii) each R⁷ is cyclopropyl; and R⁶ is chloro;    -   (xxiv) each R⁷ is cyclopropyl; and R⁶ is fluoro;    -   (xxv) each R⁷ is isopropyl; and R⁶ is methoxy;    -   (xxvi) each R⁷ is isopropyl; and R⁶ is trifluoromethoxy;    -   (xxvii) each R⁷ is chloro; and R⁶ is trifluoromethyl; or    -   (xxviii) each R⁷ is chloro; and R⁶ is trifluoromethoxy.

In some embodiments, of the compound of formula AA,

the substituted ring B is

and R⁶ and R⁷ are one of the following combinations:

-   -   (i) each R⁶ is independently C₁-C₆ alkyl, and each R⁷ is        independently C₁-C₆ alkyl optionally substituted with one or        more halo;    -   (ii) each R⁶ is independently C₁-C₆ alkyl and each R⁷ is        independently C₁-C₆ alkyl;    -   (iii) each R⁶ is independently C₁-C₆ alkyl, and each R⁷ is        independently C₁-C₆ alkyl substituted with one or more halo;    -   (iv) each R⁶ is independently C₁-C₆ alkyl, and each R⁷ is        independently C₃-C₇ cycloalkyl;    -   (v) each R⁶ is independently C₁-C₆ alkyl, and each R⁷ is        independently halo;    -   (vi) each R⁶ is independently C₁-C₆ alkyl, and R⁷ is cyano;    -   (vii) each R⁶ is independently C₃-C₇ cycloalkyl, and each R⁷ is        independently C₃-C₇ cycloalkyl;    -   (viii) each R⁶ is independently C₃-C₇ cycloalkyl, and each R⁷ is        independently halo;    -   (ix) each R⁶ is independently cyclopropyl and each R⁷ is        independently halo;    -   (x) each R⁶ is independently C₁-C₆ alkyl, and each R⁷ is        independently C₁-C₆ alkoxy optionally substituted with one or        more halo;    -   (xi) each R⁶ is independently C₁-C₆ alkyl, and each R⁷ is        independently C₁-C₆ alkoxy;    -   (xii) each R⁶ is independently C₁-C₆ alkyl, and each R⁷ is        independently C₁-C₆ alkoxy substituted with one or more halo;    -   (xiii) each R⁶ is independently halo, and each R⁷ is        independently C₁-C₆ haloalkyl;    -   (xiv) each R⁶ is independently halo, and each R⁷ is        independently C₁-C₆ haloalkoxy;    -   (xv) each R⁶ is independently C₁-C₆ alkoxy; and each R⁷ is        independently halo;    -   (xvi) each R⁶ is independently C₁-C₆ alkoxy; and R⁷ is chloro;    -   (xvii) each R⁷ is independently C₁-C₆ alkyl, and each R⁶ is        independently C₁-C₆ alkyl optionally substituted with one or        more halo;    -   (xviii) each R⁷ is independently C₁-C₆ alkyl, and each R⁶ is        independently C₁-C₆ alkyl substituted with one or more halo;    -   (xix) each R⁷ is independently C₁-C₆ alkyl, and each R⁶ is        independently C₃-C₇ cycloalkyl;    -   (xx) each R⁷ is independently C₁-C₆ alkyl, and each R⁶ is        independently halo;    -   (xxi) each R⁷ is independently C₁-C₆ alkyl and each R⁶ is        independently halo;    -   (xxii) each R⁷ is independently C₁-C₆ alkyl, and R⁶ is cyano;    -   (xxiii) each R⁷ is independently C₃-C₇ cycloalkyl, and each R⁶        is independently C₃-C₇ cycloalkyl    -   (xxiv) each R⁷ is independently C₃-C₇ cycloalkyl, and each R⁶ is        independently halo;    -   (xxv) each R⁷ is independently C₃-C₇ cycloalkyl and each R⁶ is        independently halo;    -   (xxvi) each R⁷ is independently C₁-C₆ alkyl, and each R⁶ is        independently C₁-C₆ alkoxy optionally substituted with one or        more halo;    -   (xxvii) each R⁷ is independently C₁-C₆ alkyl, and each R⁶ is        independently C₁-C₆ alkoxy;    -   (xxviii) each R⁷ is independently C₁-C₆ alkyl, and each R⁶ is        independently C₁-C₆ alkoxy substituted with one or more halo;    -   (xxix) each R⁷ is independently halo, and each R⁶ is        independently C₁-C₆ haloalkyl;    -   (xxx) each R⁷ is independently halo, and each R⁶ is        independently C₁-C₆ haloalkoxy;    -   (xxxi) each R⁷ is independently C₁-C₆ alkoxy; and each R⁶ is        independently halo;    -   (xxxii) each R⁷ is independently C₁-C₆ alkoxy; and R⁶ is chloro;    -   (xxxiii) two pairs, each of one R⁶ and one R⁷, are on adjacent        atoms, and each pair of one R⁶ and one R⁷ taken together with        the atoms connecting them form a C₄-C₈ aliphatic carbocyclic        ring;    -   (xxxiv) two pairs, each of one R⁶ and one R⁷, are on adjacent        atoms, and each pair of one R⁶ and one R⁷ taken together with        the atoms connecting them form a C₄-C₆ aliphatic carbocyclic        ring optionally substituted with one or more hydroxy, oxo, or        C₁-C₆ alkyl;    -   (xxxv) two pairs, each of one R⁶ and one R⁷, are on adjacent        atoms, and one pair of one R⁶ and one R⁷ taken together with the        atoms connecting them form a C₄-C₆ aliphatic carbocyclic ring        optionally substituted with one or more hydroxy, oxo, or C₁-C₆        alkyl, and the other pair of one R⁶ and one R⁷ taken together        with the atoms connecting them form a 5-to-6-membered        heterocyclic ring containing 1 heteroatom independently selected        from O, N, and S, wherein the heterocyclic ring is optionally        substituted with one or more hydroxy, oxo, or C₁-C₆ alkyl; or    -   (xxxvi) two pairs, each of one R⁶ and one R⁷, are on adjacent        atoms, and each pair of one R⁶ and one R⁷ taken together with        the atoms connecting them form a 5-to-6-membered heterocyclic        ring containing 1 heteroatom independently selected from O, N,        and S, wherein the heterocyclic ring optionally substituted with        one or more hydroxy, oxo, or C₁-C₆ alkyl.

In some embodiments, of the compound of formula AA,

the substituted ring B is

and R⁶ and R⁷ are one of the following combinations:

-   -   (i) each R⁶ is isopropyl; and each R⁷ is methyl;    -   (ii) each R⁶ is isopropyl; and each R⁷ is isopropyl;    -   (iii) each R⁶ is isopropyl; and each R⁷ is trifluoromethyl;    -   (iv) each R⁶ is isopropyl; and each R⁷ is cyclopropyl;    -   (v) each R⁶ is isopropyl; and each R⁷ is chloro;    -   (vi) each R⁶ is isopropyl; and each R⁷ is fluoro;    -   (vii) each R⁶ is ethyl; and each R⁷ is fluoro;    -   (viii) each R⁶ is isopropyl; and each R⁷ is cyano;    -   (ix) each R⁶ is cyclopropyl; and each R⁷ is cyclopropyl;    -   (x) each R⁶ is cyclopropyl; and each R⁷ is chloro;    -   (xi) each R⁶ is cyclopropyl; and each R⁷ is fluoro;    -   (xii) each R⁶ is isopropyl; and each R⁷ is methoxy;    -   (xiii) each R⁶ is isopropyl; and each R⁷ is trifluoromethoxy;    -   (xiv) each R⁶ is chloro; and each R⁷ is trifluoromethyl;    -   (xv) each R⁶ is chloro; and each R⁷ is trifluoromethoxy;    -   (xvi) each R⁷ is isopropyl; and each R⁶ is methyl;    -   (xvii) each R⁷ is isopropyl; and each R⁶ is trifluoromethyl;    -   (xviii) each R⁷ is isopropyl; and each R⁶ is cyclopropyl;    -   (xix) each R⁷ is isopropyl; and each R⁶ is chloro;    -   (xx) each R⁷ is ethyl; and each R⁶ is fluoro;    -   (xxi) each R⁷ is isopropyl; and each R⁶ is cyano;    -   (xxii) each R⁷ is cyclopropyl; and each R⁶ is cyclopropyl;    -   (xxiii) each R⁷ is cyclopropyl; and each R⁶ is chloro;    -   (xxiv) each R⁷ is cyclopropyl; and each R⁶ is fluoro;    -   (xxv) each R⁷ is isopropyl; and each R⁶ is methoxy;    -   (xxvi) each R⁷ is isopropyl; and each R⁶ is trifluoromethoxy;    -   (xxvii) each R⁷ is chloro; and each R⁶ is trifluoromethyl;    -   (xxviii) each R⁷ is chloro; and each R⁶ is trifluoromethoxy;    -   (xxix) one R⁶ is isopropyl; the other R⁶ is trifluoromethyl; and        each R⁷ is chloro;    -   (xxx) each R⁶ is isopropyl; one R⁷ is fluoro; and the other R⁷        is cyano;    -   (xxxi) two pairs, each of one R⁶ and one R⁷, are on adjacent        atoms, and each pair of one R⁶ and one R⁷ taken together with        the atoms connecting them form a C₅ aliphatic carbocyclic ring;    -   (xxxii) two pairs, each of one R⁶ and one R⁷, are on adjacent        atoms, and each pair of one R⁶ and one R⁷ taken together with        the atoms connecting them form a C₄ aliphatic carbocyclic ring        optionally substituted with one or more hydroxy, oxo, or methyl;    -   (xxxiii) two pairs, each of one R⁶ and one R⁷, are on adjacent        atoms, and each pair of one R⁶ and one R⁷ taken together with        the atoms connecting them form a C₅ aliphatic carbocyclic ring        optionally substituted with one or more hydroxy, oxo, or methyl;    -   (xxxiv) two pairs, each of one R⁶ and one R⁷, are on adjacent        atoms, and each pair of one R⁶ and one R⁷ taken together with        the atoms connecting them form a C₆ aliphatic carbocyclic ring        optionally substituted with one or more hydroxy, oxo, or methyl;    -   (xxxv) two pairs, each of one R⁶ and one R⁷, are on adjacent        atoms, and each pair of one R⁶ and one R⁷ taken together with        the atoms connecting them form a 5-membered heterocyclic ring        containing 1 heteroatom independently selected from O, N, and S,        wherein the heterocyclic ring is optionally substituted with one        or more hydroxy, oxo, or methyl;    -   (xxxvi) two pairs, each of one R⁶ and one R⁷, are on adjacent        atoms, and each pair of one R⁶ and one R⁷ taken together with        the atoms connecting them form a 6-membered heterocyclic ring        containing 1 heteroatom independently selected from O, N, and S,        wherein the heterocyclic ring is optionally substituted with one        or more hydroxy, oxo, or methyl; or    -   (xxxvii) two pairs, each of one R⁶ and one R⁷, are on adjacent        atoms, one pair of one R⁶ and one R⁷ taken together with the        atoms connecting them form a 5-membered heterocyclic ring        containing 1 heteroatom independently selected from O, N, and S,        wherein the heterocyclic ring is optionally substituted with one        or more hydroxy, oxo, or methyl, and the other pair of one R⁶        and one R⁷ taken together with the atoms connecting them form a        C₅ aliphatic carbocyclic ring optionally substituted with one or        more hydroxy, oxo, or methyl.

In some embodiments, of the compound of formula AA,

the substituted ring B is

and R⁶ and R⁷ are one of the following combinations:

-   -   (i) each R⁶ is independently C₁-C₆ alkyl, and each R⁷ is        independently C₁-C₆ alkyl optionally substituted with one or        more halo;    -   (ii) each R⁶ is independently C₁-C₆ alkyl and each R⁷ is        independently C₁-C₆ alkyl;    -   (iii) each R⁶ is independently C₁-C₆ alkyl, and each R⁷ is        independently C₁-C₆ alkyl substituted with one or more halo;    -   (iv) each R⁶ is independently C₁-C₆ alkyl, and each R⁷ is        independently C₃-C₇ cycloalkyl;    -   (v) each R⁶ is independently C₁-C₆ alkyl, and each R⁷ is        independently halo;    -   (vi) each R⁶ is independently C₁-C₆ alkyl, and R⁷ is cyano;    -   (vii) each R⁶ is independently C₃-C₇ cycloalkyl, and each R⁷ is        independently C₃-C₇ cycloalkyl;    -   (viii) each R⁶ is independently C₃-C₇ cycloalkyl, and each R⁷ is        independently halo;    -   (ix) each R⁶ is independently cyclopropyl and each R⁷ is        independently halo;    -   (x) each R⁶ is independently C₁-C₆ alkyl, and each R⁷ is        independently C₁-C₆ alkoxy optionally substituted with one or        more halo;    -   (xi) each R⁶ is independently C₁-C₆ alkyl, and each R⁷ is        independently C₁-C₆ alkoxy;    -   (xii) each R⁶ is independently C₁-C₆ alkyl, and each R⁷ is        independently C₁-C₆ alkoxy substituted with one or more halo;    -   (xiii) each R⁶ is independently halo, and each R⁷ is        independently C₁-C₆ haloalkyl;    -   (xiv) each R⁶ is independently halo, and each R⁷ is        independently C₁-C₆ haloalkoxy;    -   (xv) each R⁶ is independently C₁-C₆ alkoxy; and each R⁷ is        independently halo;    -   (xvi) each R⁶ is independently C₁-C₆ alkoxy; and R⁷ is chloro;    -   (xvii) each R⁷ is independently C₁-C₆ alkyl, and each R⁶ is        independently C₁-C₆ alkyl optionally substituted with one or        more halo;    -   (xviii) each R⁷ is independently C₁-C₆ alkyl, and each R⁶ is        independently C₁-C₆ alkyl substituted with one or more halo;    -   (xix) each R⁷ is independently C₁-C₆ alkyl, and each R⁶ is        independently C₃-C₇ cycloalkyl;    -   (xx) each R⁷ is independently C₁-C₆ alkyl, and each R⁶ is        independently halo;    -   (xxi) each R⁷ is independently C₁-C₆ alkyl and each R⁶ is        independently halo;    -   (xxii) each R⁷ is independently C₁-C₆ alkyl, and R⁶ is cyano;    -   (xxiii) each R⁷ is independently C₃-C₇ cycloalkyl, and each R⁶        is independently C₃-C₇ cycloalkyl;    -   (xxiv) each R⁷ is independently C₃-C₇ cycloalkyl, and each R⁶ is        independently halo;    -   (xxv) each R⁷ is independently C₃-C₇ cycloalkyl and each R⁶ is        independently halo;    -   (xxvi) each R⁷ is independently C₁-C₆ alkyl, and each R⁶ is        independently C₁-C₆ alkoxy optionally substituted with one or        more halo;    -   (xxvii) each R⁷ is independently C₁-C₆ alkyl, and each R⁶ is        independently C₁-C₆ alkoxy;    -   (xxviii) each R⁷ is independently C₁-C₆ alkyl, and each R⁶ is        independently C₁-C₆ alkoxy substituted with one or more halo;    -   (xxix) each R⁷ is independently halo, and each R⁶ is        independently C₁-C₆ haloalkyl;    -   (xxx) each R⁷ is independently halo, and each R⁶ is        independently C₁-C₆ haloalkoxy;    -   (xxxi) each R⁷ is independently C₁-C₆ alkoxy; and each R⁶ is        independently halo;    -   (xxxii) each R⁷ is independently C₁-C₆ alkoxy; and R⁶ is chloro;    -   (xxxiii) two pairs, each of one R⁶ and one R⁷, are on adjacent        atoms, and each pair of one R⁶ and one R⁷ taken together with        the atoms connecting them form a C₄-C₈ aliphatic carbocyclic        ring;    -   (xxxiv) two pairs, each of one R⁶ and one R⁷ on adjacent atoms        taken together with the atoms connecting them form a C₄-C₆        aliphatic carbocyclic ring optionally substituted with one or        more hydroxy, oxo, or C₁-C₆ alkyl; or    -   (xxxv) two pairs, each of one R⁶ and one R⁷ on adjacent atoms        taken together with the atoms connecting them form a        5-to-6-membered heterocyclic ring containing 1 heteroatom        independently selected from O, N, and S, wherein the        heterocyclic ring optionally substituted with one or more        hydroxy, oxo, or C₁-C₆ alkyl.

In some embodiments, of the compound of formula AA,

the substituted ring B is

and R⁶ and R⁷ are one of the following combinations:

-   -   (i) each R⁶ is isopropyl; and each R⁷ is methyl;    -   (ii) each R⁶ is isopropyl; and each R⁷ is isopropyl;    -   (iii) each R⁶ is isopropyl; and each R⁷ is trifluoromethyl;    -   (iv) each R⁶ is isopropyl; and each R⁷ is cyclopropyl;    -   (v) each R⁶ is isopropyl; and each R⁷ is chloro;    -   (vi) each R⁶ is isopropyl; and each R⁷ is fluoro;    -   (vii) each R⁶ is ethyl; and each R⁷ is fluoro;    -   (viii) each R⁶ is isopropyl; and each R⁷ is cyano;    -   (ix) each R⁶ is cyclopropyl; and each R⁷ is cyclopropyl;    -   (x) each R⁶ is cyclopropyl; and each R⁷ is chloro;    -   (xi) each R⁶ is cyclopropyl; and each R⁷ is fluoro;    -   (xii) each R⁶ is isopropyl; and each R⁷ is methoxy;    -   (xiii) each R⁶ is isopropyl; and each R⁷ is trifluoromethoxy;    -   (xiv) each R⁶ is chloro; and each R⁷ is trifluoromethyl;    -   (xv) each R⁶ is chloro; and each R⁷ is trifluoromethoxy;    -   (xvi) each R⁷ is isopropyl; and each R⁶ is methyl;    -   (xvii) each R⁷ is isopropyl; and each R⁶ is trifluoromethyl;    -   (xviii) each R⁷ is isopropyl; and each R⁶ is cyclopropyl;    -   (xix) each R⁷ is isopropyl; and each R⁶ is chloro;    -   (xx) each R⁷ is ethyl; and each R⁶ is fluoro;    -   (xxi) each R⁷ is isopropyl; and each R⁶ is cyano;    -   (xxii) each R⁷ is cyclopropyl; and each R⁶ is cyclopropyl;    -   (xxiii) each R⁷ is cyclopropyl; and each R⁶ is chloro;    -   (xxiv) each R⁷ is cyclopropyl; and each R⁶ is fluoro;    -   (xxv) each R⁷ is isopropyl; and each R⁶ is methoxy;    -   (xxvi) each R⁷ is isopropyl; and each R⁶ is trifluoromethoxy;    -   (xxvii) each R⁷ is chloro; and each R⁶ is trifluoromethyl;    -   (xxviii) each R⁷ is chloro; and each R⁶ is trifluoromethoxy;    -   (xxix) one R⁶ is isopropyl; the other R⁶ is trifluoromethyl; and        each R⁷ is chloro;    -   (xxx) each R⁶ is isopropyl; one R⁷ is fluoro; and the other R⁷        is cyano; or    -   (xxxi) two pairs, each of one R⁶ and one R⁷ on adjacent atoms        taken together with the atoms connecting them form a C₄        aliphatic carbocyclic ring optionally substituted with one or        more hydroxy, oxo, or methyl;    -   (xxxii) two pairs, each of one R⁶ and one R⁷ on adjacent atoms        taken together with the atoms connecting them form a C₅        aliphatic carbocyclic ring optionally substituted with one or        more hydroxy, oxo, or methyl;    -   (xxxiii) two pairs, each of one R⁶ and one R⁷ on adjacent atoms        taken together with the atoms connecting them form a C₆        aliphatic carbocyclic ring optionally substituted with one or        more hydroxy, oxo, or methyl;    -   (xxxiv) two pairs, each of one R⁶ and one R⁷ on adjacent atoms        taken together with the atoms connecting them form a 5-membered        heterocyclic ring containing 1 heteroatom independently selected        from O, N, and S, wherein the heterocyclic ring is optionally        substituted with one or more hydroxy, oxo, or methyl;    -   (xxxv) two pairs, each of one R⁶ and one R⁷ on adjacent atoms        taken together with the atoms connecting them form a 6-membered        heterocyclic ring containing 1 heteroatom independently selected        from O, N, and S, wherein the heterocyclic ring is optionally        substituted with one or more hydroxy, oxo, or methyl; or    -   (xxxvi) two pairs, each of one R⁶ and one R⁷, are on adjacent        atoms, and each pair of one R⁶ and one R⁷ taken together with        the atoms connecting them form a C₅ aliphatic carbocyclic ring.

In some embodiments, of the compound of formula AA,

the substituted ring B is

and R⁶ and R⁷ are one of the following combinations:

-   -   (i) each R⁶ is independently C₁-C₆ alkyl, and each R⁷ is        independently C₁-C₆ alkyl optionally substituted with one or        more halo;    -   (ii) each R⁶ is independently C₁-C₆ alkyl and each R⁷ is        independently C₁-C₆ alkyl;    -   (iii) each R⁶ is independently C₁-C₆ alkyl, and each R⁷ is        independently C₁-C₆ alkyl substituted with one or more halo;    -   (iv) each R⁶ is independently C₁-C₆ alkyl, and each R⁷ is        independently C₃-C₇ cycloalkyl;    -   (v) each R⁶ is independently C₁-C₆ alkyl, and each R⁷ is        independently halo;    -   (vi) each R⁶ is independently C₁-C₆ alkyl, and R⁷ is cyano;    -   (vii) each R⁶ is independently C₃-C₇ cycloalkyl, and each R⁷ is        independently C₃-C₇ cycloalkyl;    -   (viii) each R⁶ is independently C₃-C₇ cycloalkyl, and each R⁷ is        independently halo;    -   (ix) each R⁶ is independently cyclopropyl and each R⁷ is        independently halo;    -   (x) each R⁶ is independently C₁-C₆ alkyl, and each R⁷ is        independently C₁-C₆ alkoxy optionally substituted with one or        more halo;    -   (xi) each R⁶ is independently C₁-C₆ alkyl, and each R⁷ is        independently C₁-C₆ alkoxy;    -   (xii) each R⁶ is independently C₁-C₆ alkyl, and each R⁷ is        independently C₁-C₆ alkoxy substituted with one or more halo;    -   (xiii) each R⁶ is independently halo, and each R⁷ is        independently C₁-C₆ haloalkyl;    -   (xiv) each R⁶ is independently halo, and each R⁷ is        independently C₁-C₆ haloalkoxy;    -   (xv) each R⁶ is independently C₁-C₆ alkoxy; and each R⁷ is        independently halo;    -   (xvi) each R⁶ is independently C₁-C₆ alkoxy; and R⁷ is chloro;    -   (xvii) each R⁷ is independently C₁-C₆ alkyl, and each R⁶ is        independently C₁-C₆ alkyl optionally substituted with one or        more halo;    -   (xviii) each R⁷ is independently C₁-C₆ alkyl, and each R⁶ is        independently C₁-C₆ alkyl substituted with one or more halo;    -   (xix) each R⁷ is independently C₁-C₆ alkyl, and each R⁶ is        independently C₃-C₇ cycloalkyl;    -   (xx) each R⁷ is independently C₁-C₆ alkyl, and each R⁶ is        independently halo;    -   (xxi) each R⁷ is independently C₁-C₆ alkyl and each R⁶ is        independently halo;    -   (xxii) each R⁷ is independently C₁-C₆ alkyl, and R⁶ is cyano;    -   (xxiii) each R⁷ is independently C₃-C₇ cycloalkyl, and each R⁶        is independently C₃-C₇ cycloalkyl;    -   (xxiv) each R⁷ is independently C₃-C₇ cycloalkyl, and each R⁶ is        independently halo;    -   (xxv) each R⁷ is independently C₃-C₇ cycloalkyl and each R⁶ is        independently halo;    -   (xxvi) each R⁷ is independently C₁-C₆ alkyl, and each R⁶ is        independently C₁-C₆ alkoxy optionally substituted with one or        more halo;    -   (xxvii) each R⁷ is independently C₁-C₆ alkyl, and each R⁶ is        independently C₁-C₆ alkoxy;    -   (xxviii) each R⁷ is independently C₁-C₆ alkyl, and each R⁶ is        independently C₁-C₆ alkoxy substituted with one or more halo;    -   (xxix) each R⁷ is independently halo, and each R⁶ is        independently C₁-C₆ haloalkyl;    -   (xxx) each R⁷ is independently halo, and each R⁶ is        independently C₁-C₆ haloalkoxy;    -   (xxxi) each R⁷ is independently C₁-C₆ alkoxy; and each R⁶ is        independently halo; or    -   (xxxii) each R⁷ is independently C₁-C₆ alkoxy; and R⁶ is chloro.

In some embodiments of the compound of formula AA,

the substituted ring B is

and R⁶ and R⁷ are one of the following combinations:

-   -   (i) each R⁶ is isopropyl; and each R⁷ is methyl;    -   (ii) each R⁶ is isopropyl; and each R⁷ is isopropyl;    -   (iii) each R⁶ is isopropyl; and each R⁷ is trifluoromethyl;    -   (iv) each R⁶ is isopropyl; and each R⁷ is cyclopropyl;    -   (v) each R⁶ is isopropyl; and each R⁷ is chloro;    -   (vi) each R⁶ is isopropyl; and each R⁷ is fluoro;    -   (vii) each R⁶ is ethyl; and each R⁷ is fluoro;    -   (viii) each R⁶ is isopropyl; and each R⁷ is cyano;    -   (ix) each R⁶ is cyclopropyl; and each R⁷ is cyclopropyl;    -   (x) each R⁶ is cyclopropyl; and each R⁷ is chloro;    -   (xi) each R⁶ is cyclopropyl; and each R⁷ is fluoro;    -   (xii) each R⁶ is isopropyl; and each R⁷ is methoxy;    -   (xiii) each R⁶ is isopropyl; and each R⁷ is trifluoromethoxy;    -   (xiv) each R⁶ is chloro; and each R⁷ is trifluoromethyl;    -   (xv) each R⁶ is chloro; and each R⁷ is trifluoromethoxy;    -   (xvi) each R⁷ is isopropyl; and each R⁶ is methyl;    -   (xvii) each R⁷ is isopropyl; and each R⁶ is trifluoromethyl;    -   (xviii) each R⁷ is isopropyl; and each R⁶ is cyclopropyl;    -   (xix) each R⁷ is isopropyl; and each R⁶ is chloro;    -   (xx) each R⁷ is ethyl; and each R⁶ is fluoro;    -   (xxi) each R⁷ is isopropyl; and each R⁶ is cyano;    -   (xxii) each R⁷ is cyclopropyl; and each R⁶ is cyclopropyl;    -   (xxiii) each R⁷ is cyclopropyl; and each R⁶ is chloro;    -   (xxiv) each R⁷ is cyclopropyl; and each R⁶ is fluoro;    -   (xxv) each R⁷ is isopropyl; and each R⁶ is methoxy;    -   (xxvi) each R⁷ is isopropyl; and each R⁶ is trifluoromethoxy;    -   (xxvii) each R⁷ is chloro; and each R⁶ is trifluoromethyl;    -   (xxviii) each R⁷ is chloro; and each R⁶ is trifluoromethoxy;    -   (xxix) one R⁶ is isopropyl; the other R⁶ is trifluoromethyl; and        R⁷ is chloro; or    -   (xxx) R⁶ is isopropyl; one R⁷ is fluoro; and the other R⁷ is        cyano.

In some embodiments, of the compound of formula AA,

the substituted ring B is

and R⁶ and R⁷ are one of the following combinations:

-   -   each R⁶ is independently C₁-C₆ alkyl, and each R⁷ is        independently C₁-C₆ alkyl optionally substituted with one or        more halo;    -   each R⁶ is independently C₁-C₆ alkyl and each R⁷ is        independently C₁-C₆ alkyl;    -   each R⁶ is independently C₁-C₆ alkyl, and each R⁷ is        independently C₁-C₆ alkyl substituted with one or more halo;    -   each R⁶ is independently C₁-C₆ alkyl, and each R⁷ is        independently C₃-C₇ cycloalkyl;    -   each R⁶ is independently C₁-C₆ alkyl, and each R⁷ is        independently halo;    -   each R⁶ is independently C₁-C₆ alkyl, and each R⁷ is cyano;    -   each R⁶ is independently C₃-C₇ cycloalkyl, and each R⁷ is        independently C₃-C₇ cycloalkyl;    -   each R⁶ is independently C₃-C₇ cycloalkyl, and each R⁷ is        independently halo;    -   each R⁶ is independently cyclopropyl and each R⁷ is        independently halo;    -   each R⁶ is independently C₁-C₆ alkyl, and each R⁷ is        independently C₁-C₆ alkoxy optionally substituted with one or        more halo;    -   each R⁶ is independently C₁-C₆ alkyl, and each R⁷ is        independently C₁-C₆ alkoxy;    -   each R⁶ is independently C₁-C₆ alkyl, and each R⁷ is        independently C₁-C₆ alkoxy substituted with one or more halo;    -   each R⁶ is independently halo, and each R⁷ is independently        C₁-C₆ haloalkyl;    -   each R⁶ is independently halo, and each R⁷ is independently        C₁-C₆ haloalkoxy;    -   each R⁶ is independently C₁-C₆ alkoxy; and each R⁷ is        independently halo;    -   each R⁶ is independently C₁-C₆ alkoxy; and each R⁷ is chloro;    -   each R⁷ is independently C₁-C₆ alkyl, and each R⁶ is        independently C₁-C₆ alkyl optionally substituted with one or        more halo;    -   each R⁷ is independently C₁-C₆ alkyl, and each R⁶ is        independently C₁-C₆ alkyl substituted with one or more halo;    -   each R⁷ is independently C₁-C₆ alkyl, and each R⁶ is        independently C₃-C₇ cycloalkyl;    -   each R⁷ is independently C₁-C₆ alkyl, and each R⁶ is        independently halo;    -   each R⁷ is independently C₁-C₆ alkyl and each R⁶ is        independently halo;    -   each R⁷ is independently C₁-C₆ alkyl, and each R⁶ is cyano;    -   each R⁷ is independently C₃-C₇ cycloalkyl, and each R⁶ is        independently C₃-C₇ cycloalkyl;    -   each R⁷ is independently C₃-C₇ cycloalkyl, and each R⁶ is        independently halo;    -   each R⁷ is independently C₃-C₇ cycloalkyl and each R⁶ is        independently halo;    -   each R⁷ is independently C₁-C₆ alkyl, and each R⁶ is        independently C₁-C₆ alkoxy optionally substituted with one or        more halo;    -   each R⁷ is independently C₁-C₆ alkyl, and each R⁶ is        independently C₁-C₆ alkoxy;    -   each R⁷ is independently C₁-C₆ alkyl, and each R⁶ is        independently C₁-C₆ alkoxy substituted with one or more halo;    -   each R⁷ is independently halo, and each R⁶ is independently        C₁-C₆ haloalkyl;    -   each R⁷ is independently halo, and each R⁶ is independently        C₁-C₆ haloalkoxy;    -   each R⁷ is independently C₁-C₆ alkoxy; and each R⁶ is        independently halo;    -   each R⁷ is independently C₁-C₆ alkoxy; and each R⁶ is chloro;    -   R⁶ and R⁷ on adjacent atoms taken together with the atoms        connecting them form a C₄-C₆ aliphatic carbocyclic ring        optionally substituted with one or more hydroxy, oxo, or C₁-C₆        alkyl; and one R⁶ is halo or cyano; or    -   R⁶ and R⁷ on adjacent atoms taken together with the atoms        connecting them form a 5-to-6-membered heterocyclic ring        containing 1 heteroatom independently selected from O, N, and S,        wherein the heterocyclic ring optionally substituted with one or        more hydroxy, oxo, or C₁-C₆ alkyl; and one R⁶ is halo or cyano.

In some embodiments, of the compound of formula AA,

the substituted ring B is

and R⁶ and R⁷ are one of the following combinations:

-   -   each R⁶ is isopropyl; and each R⁷ is methyl;    -   each R⁶ is isopropyl; and each R⁷ is isopropyl;    -   each R⁶ is isopropyl; and each R⁷ is trifluoromethyl;    -   each R⁶ is isopropyl; and each R⁷ is cyclopropyl;    -   each R⁶ is isopropyl; and each R⁷ is chloro;    -   each R⁶ is isopropyl; and each R⁷ is fluoro;    -   each R⁶ is ethyl; and each R⁷ is fluoro;    -   each R⁶ is isopropyl; and each R⁷ is cyano;    -   each R⁶ is cyclopropyl; and each R⁷ is cyclopropyl;    -   each R⁶ is cyclopropyl; and each R⁷ is chloro;    -   each R⁶ is cyclopropyl; and each R⁷ is fluoro;    -   each R⁶ is isopropyl; and each R⁷ is methoxy;    -   each R⁶ is isopropyl; and each R⁷ is trifluoromethoxy;    -   each R⁶ is chloro; and each R⁷ is trifluoromethyl;    -   each R⁶ is chloro; and each R⁷ is trifluoromethoxy;    -   each R⁷ is isopropyl; and each R⁶ is methyl;    -   each R⁷ is isopropyl; and each R⁶ is trifluoromethyl;    -   each R⁷ is isopropyl; and each R⁶ is cyclopropyl;    -   each R⁷ is isopropyl; and each R⁶ is chloro;    -   each R⁷ is ethyl; and each R⁶ is fluoro;    -   each R⁷ is isopropyl; and each R⁶ is cyano;    -   each R⁷ is cyclopropyl; and each R⁶ is cyclopropyl;    -   each R⁷ is cyclopropyl; and each R⁶ is chloro;    -   each R⁷ is cyclopropyl; and each R⁶ is fluoro;    -   each R⁷ is isopropyl; and each R⁶ is methoxy;    -   each R⁷ is isopropyl; and each R⁶ is trifluoromethoxy;    -   each R⁷ is chloro; and each R⁶ is trifluoromethyl;    -   each R⁷ is chloro; and each R⁶ is trifluoromethoxy;

one R⁶ is isopropyl; the other R⁶ is trifluoromethyl; and each R⁷ ischloro;

-   -   each R⁶ is isopropyl; one R⁷ is fluoro; and the other R⁷ is        cyano;    -   R⁶ and R⁷ on adjacent atoms taken together with the atoms        connecting them form a C₄ aliphatic carbocyclic ring; and one R⁶        is chloro, fluoro, or cyano;    -   R⁶ and R⁷ on adjacent atoms taken together with the atoms        connecting them form a C₅ aliphatic carbocyclic ring; and one R⁶        is chloro, fluoro, or cyano;    -   R⁶ and R⁷ on adjacent atoms taken together with the atoms        connecting them form a C₆ aliphatic carbocyclic ring; and one R⁶        is chloro, fluoro, or cyano;    -   R⁶ and R⁷ on adjacent atoms taken together with the atoms        connecting them form a 5-membered heterocyclic ring containing 1        heteroatoms independently selected from O, N, and S; and one R⁶        is chloro, fluoro, or cyano;    -   R⁶ and R⁷ on adjacent atoms taken together with the atoms        connecting them form a 6-membered heterocyclic ring containing 1        heteroatoms independently selected from O, N, and S; and one R⁶        is chloro, fluoro, or cyano; or    -   R⁶ and R⁷ on adjacent atoms taken together with the atoms        connecting them form a C₅ aliphatic carbocyclic ring; and one R⁶        is chloro, fluoro, or cyano.

In some embodiments, of the compound of formula AA,

the substituted ring B is

and R⁶ and R⁷ are one of the following combinations:

-   -   (i) each R⁶ is independently C₁-C₆ alkyl, and each R⁷ is        independently C₁-C₆ alkyl optionally substituted with one or        more halo;    -   (ii) each R⁶ is independently C₁-C₆ alkyl and each R⁷ is        independently C₁-C₆ alkyl;    -   (iii) each R⁶ is independently C₁-C₆ alkyl, and each R⁷ is        independently C₁-C₆ alkyl substituted with one or more halo;    -   (iv) each R⁶ is independently C₁-C₆ alkyl, and each R⁷ is        independently C₃-C₇ cycloalkyl;    -   (v) each R⁶ is independently C₁-C₆ alkyl, and each R⁷ is        independently halo;    -   (vi) each R⁶ is independently C₁-C₆ alkyl, and R⁷ is cyano;    -   (vii) each R⁶ is independently C₃-C₇ cycloalkyl, and each R⁷ is        independently C₃-C₇ cycloalkyl;    -   (viii) each R⁶ is independently C₃-C₇ cycloalkyl, and each R⁷ is        independently halo;    -   (ix) each R⁶ is independently cyclopropyl and each R⁷ is        independently halo;    -   (x) each R⁶ is independently C₁-C₆ alkyl, and each R⁷ is        independently C₁-C₆ alkoxy optionally substituted with one or        more halo;    -   (xi) each R⁶ is independently C₁-C₆ alkyl, and each R⁷ is        independently C₁-C₆ alkoxy;    -   (xii) each R⁶ is independently C₁-C₆ alkyl, and each R⁷ is        independently C₁-C₆ alkoxy substituted with one or more halo;    -   (xiii) each R⁶ is independently halo, and each R⁷ is        independently C₁-C₆ haloalkyl;    -   (xiv) each R⁶ is independently halo, and each R⁷ is        independently C₁-C₆ haloalkoxy;    -   (xv) each R⁶ is independently C₁-C₆ alkoxy; and each R⁷ is        independently halo;    -   (xvi) each R⁶ is independently C₁-C₆ alkoxy; and R⁷ is chloro;    -   (xvii) each R⁷ is independently C₁-C₆ alkyl, and each R⁶ is        independently C₁-C₆ alkyl optionally substituted with one or        more halo;    -   (xviii) each R⁷ is independently C₁-C₆ alkyl, and each R⁶ is        independently C₁-C₆ alkyl substituted with one or more halo;    -   (xix) each R⁷ is independently C₁-C₆ alkyl, and each R⁶ is        independently C₃-C₇ cycloalkyl;    -   (xx) each R⁷ is independently C₁-C₆ alkyl, and each R⁶ is        independently halo;    -   (xxi) each R⁷ is independently C₁-C₆ alkyl and each R⁶ is        independently halo;    -   (xxii) each R⁷ is independently C₁-C₆ alkyl, and R⁶ is cyano;    -   (xxiii) each R⁷ is independently C₃-C₇ cycloalkyl, and each R⁶        is independently C₃-C₇ cycloalkyl;    -   (xxiv) each R⁷ is independently C₃-C₇ cycloalkyl, and each R⁶ is        independently halo;    -   (xxv) each R⁷ is independently C₃-C₇ cycloalkyl and each R⁶ is        independently halo;    -   (xxvi) each R⁷ is independently C₁-C₆ alkyl, and each R⁶ is        independently C₁-C₆ alkoxy optionally substituted with one or        more halo;    -   (xxvii) each R⁷ is independently C₁-C₆ alkyl, and each R⁶ is        independently C₁-C₆ alkoxy;    -   (xxviii) each R⁷ is independently C₁-C₆ alkyl, and each R⁶ is        independently C₁-C₆ alkoxy substituted with one or more halo;    -   (xxix) each R⁷ is independently halo, and each R⁶ is        independently C₁-C₆ haloalkyl;    -   (xxx) each R⁷ is independently halo, and each R⁶ is        independently C₁-C₆ haloalkoxy;    -   (xxxi) each R⁷ is independently C₁-C₆ alkoxy; and each R⁶ is        independently halo; or    -   (xxxii) each R⁷ is independently C₁-C₆ alkoxy; and R⁶ is chloro.

In some embodiments, of the compound of formula AA,

the substituted ring B is

and R⁶ and R⁷ are one of the following combinations:

-   -   (i) each R⁶ is isopropyl; and each R⁷ is methyl;    -   (ii) each R⁶ is isopropyl; and each R⁷ is isopropyl;    -   (iii) each R⁶ is isopropyl; and each R⁷ is trifluoromethyl;    -   (iv) each R⁶ is isopropyl; and each R⁷ is cyclopropyl;    -   (v) each R⁶ is isopropyl; and each R⁷ is chloro;    -   (vi) each R⁶ is isopropyl; and each R⁷ is fluoro;    -   (vii) each R⁶ is ethyl; and each R⁷ is fluoro;    -   (viii) each R⁶ is isopropyl; and each R⁷ is cyano;    -   (ix) each R⁶ is cyclopropyl; and each R⁷ is cyclopropyl;    -   (x) each R⁶ is cyclopropyl; and each R⁷ is chloro;    -   (xi) each R⁶ is cyclopropyl; and each R⁷ is fluoro;    -   (xii) each R⁶ is isopropyl; and each R⁷ is methoxy;    -   (xiii) each R⁶ is isopropyl; and each R⁷ is trifluoromethoxy;    -   (xiv) each R⁶ is chloro; and each R⁷ is trifluoromethyl;    -   (xv) each R⁶ is chloro; and each R⁷ is trifluoromethoxy;    -   (xvi) each R⁷ is isopropyl; and each R⁶ is methyl;    -   (xvii) each R⁷ is isopropyl; and each R⁶ is trifluoromethyl;    -   (xviii) each R⁷ is isopropyl; and each R⁶ is cyclopropyl;    -   (xix) each R⁷ is isopropyl; and each R⁶ is chloro;    -   (xx) each R⁷ is ethyl; and each R⁶ is fluoro;    -   (xxi) each R⁷ is isopropyl; and each R⁶ is cyano;    -   (xxii) each R⁷ is cyclopropyl; and each R⁶ is cyclopropyl;    -   (xxiii) each R⁷ is cyclopropyl; and each R⁶ is chloro;    -   (xxiv) each R⁷ is cyclopropyl; and each R⁶ is fluoro;    -   (xxv) each R⁷ is isopropyl; and each R⁶ is methoxy;    -   (xxvi) each R⁷ is isopropyl; and each R⁶ is trifluoromethoxy;    -   (xxvii) each R⁷ is chloro; and each R⁶ is trifluoromethyl;    -   (xxviii) each R⁷ is chloro; and each R⁶ is trifluoromethoxy;    -   (xxix) one R⁶ is isopropyl; the other R⁶ is trifluoromethyl; and        each R⁷ is chloro; or    -   (xxx) each R⁶ is isopropyl; one R⁷ is fluoro; and the other R⁷        is cyano.

In some embodiments, of the compound of formula AA,

the substituted ring B is

and R⁶ and R⁷ are one of the following combinations:

-   -   (i) each R⁶ is independently C₁-C₆ alkyl, and each R⁷ is        independently C₁-C₆ alkyl optionally substituted with one or        more halo;    -   (ii) each R⁶ is independently C₁-C₆ alkyl and each R⁷ is        independently C₁-C₆ alkyl;    -   (iii) each R⁶ is independently C₁-C₆ alkyl, and each R⁷ is        independently C₁-C₆ alkyl substituted with one or more halo;    -   (iv) each R⁶ is independently C₁-C₆ alkyl, and each R⁷ is        independently C₃-C₇ cycloalkyl;    -   (v) each R⁶ is independently C₁-C₆ alkyl, and each R⁷ is        independently halo;    -   (vi) each R⁶ is independently C₁-C₆ alkyl, and R⁷ is cyano;    -   (vii) each R⁶ is independently C₃-C₇ cycloalkyl, and each R⁷ is        independently C₃-C₇ cycloalkyl;    -   (viii) each R⁶ is independently C₃-C₇ cycloalkyl, and each R⁷ is        independently halo;    -   (ix) each R⁶ is independently cyclopropyl and each R⁷ is        independently halo;    -   (x) each R⁶ is independently C₁-C₆ alkyl, and each R⁷ is        independently C₁-C₆ alkoxy optionally substituted with one or        more halo;    -   (xi) each R⁶ is independently C₁-C₆ alkyl, and each R⁷ is        independently C₁-C₆ alkoxy;    -   (xii) each R⁶ is independently C₁-C₆ alkyl, and each R⁷ is        independently C₁-C₆ alkoxy substituted with one or more halo;    -   (xiii) each R⁶ is independently halo, and each R⁷ is        independently C₁-C₆ haloalkyl;    -   (xiv) each R⁶ is independently halo, and each R⁷ is        independently C₁-C₆ haloalkoxy;    -   (xv) each R⁶ is independently C₁-C₆ alkoxy; and each R⁷ is        independently halo;    -   (xvi) each R⁶ is independently C₁-C₆ alkoxy; and R⁷ is chloro;    -   (xvii) each R⁷ is independently C₁-C₆ alkyl, and each R⁶ is        independently C₁-C₆ alkyl optionally substituted with one or        more halo;    -   (xviii) each R⁷ is independently C₁-C₆ alkyl, and each R⁶ is        independently C₁-C₆ alkyl substituted with one or more halo;    -   (xix) each R⁷ is independently C₁-C₆ alkyl, and each R⁶ is        independently C₃-C₇ cycloalkyl;    -   (xx) each R⁷ is independently C₁-C₆ alkyl, and each R⁶ is        independently halo;    -   (xxi) each R⁷ is independently C₁-C₆ alkyl and each R⁶ is        independently halo;    -   (xxii) each R⁷ is independently C₁-C₆ alkyl, and R⁶ is cyano;    -   (xxiii) each R⁷ is independently C₃-C₇ cycloalkyl, and each R⁶        is independently C₃-C₇ cycloalkyl;    -   (xxiv) each R⁷ is independently C₃-C₇ cycloalkyl, and each R⁶ is        independently halo;    -   (xxv) each R⁷ is independently C₃-C₇ cycloalkyl and each R⁶ is        independently halo;    -   (xxvi) each R⁷ is independently C₁-C₆ alkyl, and each R⁶ is        independently C₁-C₆ alkoxy optionally substituted with one or        more halo;    -   (xxvii) each R⁷ is independently C₁-C₆ alkyl, and each R⁶ is        independently C₁-C₆ alkoxy;    -   (xxviii) each R⁷ is independently C₁-C₆ alkyl, and each R⁶ is        independently C₁-C₆ alkoxy substituted with one or more halo;    -   (xxix) each R⁷ is independently halo, and each R⁶ is        independently C₁-C₆ haloalkyl;    -   (xxx) each R⁷ is independently halo, and each R⁶ is        independently C₁-C₆ haloalkoxy;    -   (xxxi) each R⁷ is independently C₁-C₆ alkoxy; and each R⁶ is        independently halo;    -   (xxxvi) each R⁷ is independently C₁-C₆ alkoxy; and R⁶ is chloro;    -   (xxxvii) two pairs, each of one R⁶ and one R⁷, are on adjacent        atoms, and each pair of one R⁶ and one R⁷ taken together with        the atoms connecting them form a C₄-C₆ aliphatic carbocyclic        ring optionally substituted with one or more hydroxy, oxo, or        C₁-C₆ alkyl;    -   (xxxii) two pairs, each of one R⁶ and one R⁷, are on adjacent        atoms, and each pair of one R⁶ and one R⁷ taken together with        the atoms connecting them form a 5-to-6-membered heterocyclic        ring containing 1 heteroatom independently selected from O, N,        and S, wherein the heterocyclic ring optionally substituted with        one or more hydroxy, oxo, or C₁-C₆ alkyl; or    -   (xxxiii) two pairs, each of one R⁶ and one R⁷, are on adjacent        atoms, one pair of one R⁶ and one R⁷ taken together with the        atoms connecting them form a C₄-C₆ aliphatic carbocyclic ring        optionally substituted with one or more hydroxy, oxo, or C₁-C₆        alkyl, and the other pair of one R⁶ and one R⁷ taken together        with the atoms connecting them form a 5-to-6-membered        heterocyclic ring containing 1 heteroatom independently selected        from O, N, and S, wherein the heterocyclic ring optionally        substituted with one or more hydroxy, oxo, or C₁-C₆ alkyl.

In some embodiments, of the compound of formula AA,

the substituted ring B is

and R⁶ and R⁷ are one of the following combinations:

-   -   (i) each R⁶ is isopropyl; and each R⁷ is methyl;    -   (ii) each R⁶ is isopropyl; and each R⁷ is isopropyl;    -   (iii) each R⁶ is isopropyl; and each R⁷ is trifluoromethyl;    -   (iv) each R⁶ is isopropyl; and each R⁷ is cyclopropyl;    -   (v) each R⁶ is isopropyl; and each R⁷ is chloro;    -   (vi) each R⁶ is isopropyl; and each R⁷ is fluoro;    -   (vii) each R⁶ is ethyl; and each R⁷ is fluoro;    -   (viii) each R⁶ is isopropyl; and each R⁷ is cyano;    -   (ix) each R⁶ is cyclopropyl; and each R⁷ is cyclopropyl;    -   (x) each R⁶ is cyclopropyl; and each R⁷ is chloro;    -   (xi) each R⁶ is cyclopropyl; and each R⁷ is fluoro;    -   (xii) each R⁶ is isopropyl; and each R⁷ is methoxy;    -   (xiii) each R⁶ is isopropyl; and each R⁷ is trifluoromethoxy;    -   (xiv) each R⁶ is chloro; and each R⁷ is trifluoromethyl;    -   (xv) each R⁶ is chloro; and each R⁷ is trifluoromethoxy;    -   (xvi) each R⁷ is isopropyl; and each R⁶ is methyl;    -   (xvii) each R⁷ is isopropyl; and each R⁶ is trifluoromethyl;    -   (xviii) each R⁷ is isopropyl; and each R⁶ is cyclopropyl;    -   (xix) each R⁷ is isopropyl; and each R⁶ is chloro;    -   (xx) each R⁷ is ethyl; and each R⁶ is fluoro;    -   (xxi) each R⁷ is isopropyl; and each R⁶ is cyano;    -   (xxii) each R⁷ is cyclopropyl; and each R⁶ is cyclopropyl;    -   (xxiii) each R⁷ is cyclopropyl; and each R⁶ is chloro;    -   (xxiv) each R⁷ is cyclopropyl; and each R⁶ is fluoro;    -   (xxv) each R⁷ is isopropyl; and each R⁶ is methoxy;    -   (xxvi) each R⁷ is isopropyl; and each R⁶ is trifluoromethoxy;    -   (xxvii) R⁷ is chloro; and each R⁶ is trifluoromethyl;    -   (xxviii) R⁷ is chloro; and each R⁶ is trifluoromethoxy;    -   (xxix) one R⁶ is isopropyl; the other R⁶ is trifluoromethyl; and        R⁷ is chloro;    -   (xxx) R⁶ is isopropyl; one R⁷ is fluoro; and the other R⁷ is        cyano; two pairs, each of one R⁶ and one R⁷, are on adjacent        atoms, and each pair of one R⁶ and one R⁷ taken together with        the atoms connecting them form a C₅ aliphatic carbocyclic ring;    -   (xxxi) two pairs, each of one R⁶ and one R⁷, are on adjacent        atoms, and each pair of one R⁶ and one R⁷ taken together with        the atoms connecting them form a C₄ aliphatic carbocyclic ring        optionally substituted with one or more hydroxy, oxo, or methyl;    -   (xxxii) two pairs, each of one R⁶ and one R⁷, are on adjacent        atoms, and each pair of one R⁶ and one R⁷ taken together with        the atoms connecting them form a C₅ aliphatic carbocyclic ring        optionally substituted with one or more hydroxy, oxo, or methyl;    -   (xxxiii) two pairs, each of one R⁶ and one R⁷, are on adjacent        atoms, and each pair of one R⁶ and one R⁷ taken together with        the atoms connecting them form a C₆ aliphatic carbocyclic ring        optionally substituted with one or more hydroxy, oxo, or methyl;    -   (xxxiv) two pairs, each of one R⁶ and one R⁷, are on adjacent        atoms, and each pair of one R⁶ and one R⁷ taken together with        the atoms connecting them form a 5-membered heterocyclic ring        containing 1 heteroatom independently selected from O, N, and S,        wherein the heterocyclic ring is optionally substituted with one        or more hydroxy, oxo, or methyl    -   (xxxv) two pairs, each of one R⁶ and one R⁷, are on adjacent        atoms, and each pair of one R⁶ and one R⁷ taken together with        the atoms connecting them form a 6-membered heterocyclic ring        containing 1 heteroatom independently selected from O, N, and S,        wherein the heterocyclic ring is optionally substituted with one        or more hydroxy, oxo, or methyl; or    -   (xxxvi) two pairs, each of one R⁶ and one R⁷, are on adjacent        atoms, one pair of one R⁶ and one R⁷ taken together with the        atoms connecting them form a 5-membered heterocyclic ring        containing 1 heteroatom independently selected from O, N, and S,        wherein the heterocyclic ring is optionally substituted with one        or more hydroxy, oxo, or methyl, and the other pair of one R⁶        and one R⁷ taken together with the atoms connecting them form a        C₅ aliphatic carbocyclic ring optionally substituted with one or        more hydroxy, oxo, or methyl.

In some embodiments, of the compound of formula AA,

the substituted ring B is

and R⁶ and R⁷ are one of the following combinations:

-   -   (i) each R⁶ is independently C₁-C₆ alkyl, and R⁷ is C₁-C₆ alkyl        optionally substituted with one or more halo;    -   (ii) each R⁶ is independently C₁-C₆ alkyl and R⁷ is C₁-C₆ alkyl;    -   (iii) each R⁶ is independently C₁-C₆ alkyl, and R⁷ is C₁-C₆        alkyl substituted with one or more halo;    -   (iv) each R⁶ is independently C₁-C₆ alkyl, and R⁷ is C₃-C₇        cycloalkyl;    -   (v) each R⁶ is independently C₁-C₆ alkyl, and R⁷ is halo;    -   (vi) each R⁶ is independently C₁-C₆ alkyl, and R⁷ is cyano;    -   (vii) each R⁶ is independently C₃-C₇ cycloalkyl, and R⁷ is C₃-C₇        cycloalkyl;    -   (viii) each R⁶ is independently C₃-C₇ cycloalkyl, and R⁷ is        halo;    -   (ix) each R⁶ is independently cyclopropyl and R⁷ is halo;    -   (x) each R⁶ is independently C₁-C₆ alkyl, and R⁷ is C₁-C₆ alkoxy        optionally substituted with one or more halo;    -   (xi) each R⁶ is independently C₁-C₆ alkyl, and R⁷ is C₁-C₆        alkoxy;    -   (xii) each R⁶ is independently C₁-C₆ alkyl, and R⁷ is C₁-C₆        alkoxy substituted with one or more halo;    -   (xiii) each R⁶ is independently halo, and R⁷ is C₁-C₆ haloalkyl;    -   (xiv) each R⁶ is independently halo, and R⁷ is C₁-C₆ haloalkoxy;    -   (xv) each R⁶ is independently C₁-C₆ alkoxy; and R⁷ is halo;    -   (xvi) each R⁶ is independently C₁-C₆ alkoxy; and R⁷ is chloro;    -   (xvii) R⁷ is C₁-C₆ alkyl, and each R⁶ is independently C₁-C₆        alkyl optionally substituted with one or more halo;    -   (xviii) R⁷ is C₁-C₆ alkyl, and each R⁶ is independently C₁-C₆        alkyl substituted with one or more halo;    -   (xix) R⁷ is C₁-C₆ alkyl, and each R⁶ is independently C₃-C₇        cycloalkyl;    -   (xx) R⁷ is C₁-C₆ alkyl, and each R⁶ is independently halo;    -   (xxi) R⁷ is C₁-C₆ alkyl and each R⁶ is independently halo;    -   (xxii) R⁷ is C₁-C₆ alkyl, and R⁶ is cyano;    -   (xxiii) R⁷ is C₃-C₇ cycloalkyl, and each R⁶ is independently        C₃-C₇ cycloalkyl;    -   (xxiv) R⁷ is C₃-C₇ cycloalkyl, and each R⁶ is independently        halo;    -   (xxv) R⁷ is C₃-C₇ cycloalkyl and each R⁶ is independently halo;    -   (xxvi) R⁷ is C₁-C₆ alkyl, and each R⁶ is independently C₁-C₆        alkoxy optionally substituted with one or more halo;    -   (xxvii) R⁷ is C₁-C₆ alkyl, and each R⁶ is independently C₁-C₆        alkoxy;    -   (xxviii) R⁷ is C₁-C₆ alkyl, and each R⁶ is independently C₁-C₆        alkoxy substituted with one or more halo;    -   (xxix) R⁷ is halo, and each R⁶ is independently C₁-C₆ haloalkyl;    -   (xxx) R⁷ is halo, and each R⁶ is independently C₁-C₆ haloalkoxy;    -   (xxxi) R⁷ is C₁-C₆ alkoxy; and each R⁶ is independently halo;    -   (xxxii) R⁷ is C₁-C₆ alkoxy; and R⁶ is chloro;    -   (xxxiii) two pairs, each of one R⁶ and one R⁷, are on adjacent        atoms, and each pair of one R⁶ and one R⁷ taken together with        the atoms connecting them form a C₄-C₈ aliphatic carbocyclic        ring; and one R⁷ is halo;    -   (xxxiv) two pairs, each of one R⁶ and one R⁷, are on adjacent        atoms, and each pair of one R⁶ and one R⁷ taken together with        the atoms connecting them form a C₄-C₈ aliphatic carbocyclic        ring; and one R⁷ is cyano;    -   (xxxv) two pairs, each of one R⁶ and one R⁷, are on adjacent        atoms, and each pair of one R⁶ and one R⁷ taken together with        the atoms connecting them form a C₄-C₆ aliphatic carbocyclic        ring optionally substituted with one or more hydroxy, oxo, or        C₁-C₆ alkyl; and one R⁷ is halo or cyano;    -   (xxxvi) two pairs, each of one R⁶ and one R⁷, are on adjacent        atoms, and each pair of one R⁶ and one R⁷ taken together with        the atoms connecting them form a 5-to-6-membered heterocyclic        ring containing 1 heteroatom independently selected from O, N,        and S, wherein the heterocyclic ring optionally substituted with        one or more hydroxy, oxo, or C₁-C₆ alkyl; and one R⁷ is halo or        cyano; or    -   (xxxvii) two pairs, each of one R⁶ and one R⁷, are on adjacent        atoms, one pair of one R⁶ and one R⁷ taken together with the        atoms connecting them form a C₄-C₆ aliphatic carbocyclic ring        optionally substituted with one or more hydroxy, oxo, or C₁-C₆        alkyl, and the other pair of one R⁶ and one R⁷ taken together        with the atoms connecting them form a 5-to-6-membered        heterocyclic ring containing 1 heteroatom independently selected        from O, N, and S, wherein the heterocyclic ring optionally        substituted with one or more hydroxy, oxo, or C₁-C₆ alkyl; and        one R⁷ is halo or cyano.

In some embodiments, of the compound of formula AA,

the substituted ring B is

and R⁶ and R⁷ are one of the following combinations:

-   -   (i) each R⁶ is isopropyl; and each R⁷ is methyl;    -   (ii) each R⁶ is isopropyl; and each R⁷ is isopropyl;    -   (iii) each R⁶ is isopropyl; and each R⁷ is trifluoromethyl;    -   (iv) each R⁶ is isopropyl; and each R⁷ is cyclopropyl;    -   (v) each R⁶ is isopropyl; and each R⁷ is chloro;    -   (vi) each R⁶ is isopropyl; and each R⁷ is fluoro;    -   (vii) each R⁶ is ethyl; and each R⁷ is fluoro;    -   (viii) each R⁶ is isopropyl; and each R⁷ is cyano;    -   (ix) each R⁶ is cyclopropyl; and each R⁷ is cyclopropyl;    -   (x) each R⁶ is cyclopropyl; and each R⁷ is chloro;    -   (xi) each R⁶ is cyclopropyl; and each R⁷ is fluoro;    -   (xii) each R⁶ is isopropyl; and each R⁷ is methoxy;    -   (xiii) each R⁶ is isopropyl; and each R⁷ is trifluoromethoxy;    -   (xiv) each R⁶ is chloro; and each R⁷ is trifluoromethyl;    -   (xv) each R⁶ is chloro; and each R⁷ is trifluoromethoxy;    -   (xvi) each R⁷ is isopropyl; and each R⁶ is methyl;    -   (xvii) each R⁷ is isopropyl; and each R⁶ is trifluoromethyl;    -   (xviii) each R⁷ is isopropyl; and each R⁶ is cyclopropyl;    -   (xix) each R⁷ is isopropyl; and each R⁶ is chloro;    -   (xx) each R⁷ is ethyl; and each R⁶ is fluoro;    -   (xxi) each R⁷ is isopropyl; and each R⁶ is cyano;    -   (xxii) each R⁷ is cyclopropyl; and each R⁶ is cyclopropyl;    -   (xxiii) each R⁷ is cyclopropyl; and each R⁶ is chloro;    -   (xxiv) each R⁷ is cyclopropyl; and each R⁶ is fluoro;    -   (xxv) each R⁷ is isopropyl; and each R⁶ is methoxy;    -   (xxvi) each R⁷ is isopropyl; and each R⁶ is trifluoromethoxy;    -   (xxvii) each R⁷ is chloro; and each R⁶ is trifluoromethyl;    -   (xxviii) each R⁷ is chloro; and each R⁶ is trifluoromethoxy;    -   (xxix) each R⁶ is isopropyl; two R⁷ are fluoro; and one R⁷ is        chloro;    -   (xxx) two pairs, each of one R⁶ and one R⁷, are on adjacent        atoms, and each pair of one R⁶ and one R⁷ taken together with        the atoms connecting them form a C₅ aliphatic carbocyclic ring;        and one R⁷ is chloro;    -   (xxxi) two pairs, each of one R⁶ and one R⁷, are on adjacent        atoms, and each pair of one R⁶ and one R⁷ taken together with        the atoms connecting them form a C₅ aliphatic carbocyclic ring;        and one R⁷ is fluoro;    -   (xxxii) two pairs, each of one R⁶ and one R⁷, are on adjacent        atoms, and each pair of one R⁶ and one R⁷ taken together with        the atoms connecting them form a C₄ aliphatic carbocyclic ring        optionally substituted with one or more hydroxy, oxo, or methyl;        and one R⁷ is fluoro or chloro;    -   (xxxiii) two pairs, each of one R⁶ and one R⁷, are on adjacent        atoms, and each pair of one R⁶ and one R⁷ taken together with        the atoms connecting them form a C₅ aliphatic carbocyclic ring        optionally substituted with one or more hydroxy, oxo, or methyl;        and one R⁷ is fluoro or chloro;    -   (xxxiv) two pairs, each of one R⁶ and one R⁷, are on adjacent        atoms, and each pair of one R⁶ and one R⁷ taken together with        the atoms connecting them form a C₆ aliphatic carbocyclic ring        optionally substituted with one or more hydroxy, oxo, or methyl;        and one R⁷ is fluoro or chloro;    -   (xxxv) two pairs, each of one R⁶ and one R⁷, are on adjacent        atoms, and each pair of one R⁶ and one R⁷ taken together with        the atoms connecting them form a 5-membered heterocyclic ring        containing 1 heteroatom independently selected from O, N, and S,        wherein the heterocyclic ring is optionally substituted with one        or more hydroxy, oxo, or methyl; and one R⁷ is fluoro or chloro;    -   (xxxvi) two pairs, each of one R⁶ and one R⁷, are on adjacent        atoms, and each pair of one R⁶ and one R⁷ taken together with        the atoms connecting them form a 6-membered heterocyclic ring        containing 1 heteroatom independently selected from O, N, and S,        wherein the heterocyclic ring is optionally substituted with one        or more hydroxy, oxo, or methyl; and one R⁷ is fluoro or chloro;        or    -   (xxxvii) two pairs, each of one R⁶ and one R⁷, are on adjacent        atoms, one pair of one R⁶ and one R⁷ taken together with the        atoms connecting them form a 5-membered heterocyclic ring        containing 1 heteroatom independently selected from O, N, and S,        wherein the heterocyclic ring is optionally substituted with one        or more hydroxy, oxo, or methyl, and the other pair of one R⁶        and one R⁷ taken together with the atoms connecting them form a        C₅ aliphatic carbocyclic ring optionally substituted with one or        more hydroxy, oxo, or methyl; and one R⁷ is fluoro or chloro.

Additional Features of the Embodiments Herein

In some embodiments of the compound of Formula AA (e.g., Formula AA-1,Formula AA-2, Formula AA-3, Formula AA-4, or Formula AA-5), R⁶ is notCN.

In some embodiments, the compound of Formula AA is not a compoundselected from the group consisting of:

In some embodiments, the compound of Formula AA is not a compoundselected from the group consisting of:

In some embodiments the compound of any of the formulae herein is not acompound disclosed in EP 0173498, which is incorporated herein byreference in its entirety.

In some embodiments the compound of any of the formulae herein is not acompound disclosed in U.S. Pat. No. 4,666,506, which is incorporatedherein by reference in its entirety.

It is understood that the combination of variables in the formulaeherein is such that the compounds are stable.

In some embodiments, provided herein is a compound that is selected fromthe group consisting of the compounds in Table 1:

TABLE 1 Compound Structure 101′

101

102

103′

103

104

105

105a

105b

106

106a

106b

107

107a

107b

108

108a

108b

109

109a

109b

110

110a

110b

111

112

112a

112b

113

113a

113b

114

115

116

116a

116b

117

118

119

120

120a

120b

121

121a

121b

122

122a

122b

123

124

125

125a

125b

126

127

128

129

129a

129b

130

130a

130b

131

131a

131b

132

133

134

134a

134b

135

135a

135b

136

136a

136b

137

137a

137b

138

138a

138b

139

139a

139b

140

141

142

143

143a

143b

144

144a

144b

145

145a

145b

146

147

148

148a

148b

149

149a

149b

150

151a′

151b′

151

151a

151b

152

152a

152b

153

153a

153b

154

154a

154b

155

156

157

157a

157b

158

158a

158b

159

159a

159ba

159ab

160

161

161a

161b

162

163

164

165

165a

165b

166

167

167a

167b

168

168a

168b

170

170a

170b

171

171a

171b

172

172a

172b

173

173a

173b

174

174a

174b

176

176a

176b

177

177a

177b

178

178a

178b

179

179a

179b

180

180a

180b

181

181a

181b

182

182a

182b

183

183a

183b

184

185

185a

185b

186

186a

186b

187

187a

187b

188

188a

188b

189

189a

189b

190

190a

190b

191

191a

191b

192

192a

192b

193

193a

193b

194

195

195a

195ba

195bb

195e

196

197

198

199

200

201

202

202a

202b

203

204

205

205a

205b

206

206a

206b

207

207a

207b

207bb

207aa

207c

208

209

210

211

212

212a

212b

213

214

215

216

217

218

219

220

220a

220b

221

223

223a

223b

225

225a

225b

226

227

228

229

230

231

232

233

234

235

236

237

238

239

240

241

242

243

244

245

246

247

248

249

250

251

252

253

254

255

256

257

258

259

260

261

262

263

264

265

266

267

268

269

270

and pharmaceutically acceptable salts thereof.

In some embodiments, provided herein is a compound that is selected fromthe group consisting of the compounds in the following table:

303

303a

303b

306

307

308

308a

308b

309

310

311

312

313

314

315

315b

315a

316

316a

316b

317

317ab

317aa

317bb

317ba

318

318a

318b

319

319ab

319ba

319aa

319bb

320

320a

320b

321

321b

321a

322

323

323ab

323aa

323bb

323ba

324

325

325a

325b

326

326b

326a

327

328b

328a

329

329a

329b

330

330a

330b

331

332

332a

332b

333

333a

333b

334

334ba

334bb

334aa

334ab

334b

334a

335

335b

335a

336

336a

336b

337

337a

337b

338

338a

338b

339

339a

339b

340

340a

340b

341

341b

341a

342

343

343a

343b

344

345

346

347

348

349

350

351

352

352b

352a

353

354

354a

354b

355

356

357

357a

357b

358

359

359a

359b

360ba

360bb

361b

361a

363b

363a

364a

364b

365a

365b

366a

366b

367a

367b

369a

369b

371a

371b

372a

372b

373a

373b

374a

374b

375

375a

375b

376

376a

376b

377

378

379

379a

379b

380

380a

380b

380c

380d

382

382a

382b

383

383a

383b

384a

384b

387a

387b

and pharmaceutically acceptable salts thereof.

In some embodiments, provided herein is a compound that is selected fromthe group consisting of the compounds in the following table:

401

402

403

404

404a

404b

405

406

407

408

409

409a

409b

410

Pharmaceutical Compositions and Administration

General

In some embodiments, a chemical entity (e.g., a compound that modulates(e.g., antagonizes) NLRP3, or a pharmaceutically acceptable salt, and/orhydrate, and/or cocrystal, and/or drug combination thereof) isadministered as a pharmaceutical composition that includes the chemicalentity and one or more pharmaceutically acceptable excipients, andoptionally one or more additional therapeutic agents as describedherein.

In some embodiments, the chemical entities can be administered incombination with one or more conventional pharmaceutical excipients.Pharmaceutically acceptable excipients include, but are not limited to,ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifyingdrug delivery systems (SEDDS) such as d-α-tocopherol polyethylene glycol1000 succinate, surfactants used in pharmaceutical dosage forms such asTweens, poloxamers or other similar polymeric delivery matrices, serumproteins, such as human serum albumin, buffer substances such asphosphates, tris, glycine, sorbic acid, potassium sorbate, partialglyceride mixtures of saturated vegetable fatty acids, water, salts orelectrolytes, such as protamine sulfate, disodium hydrogen phosphate,potassium hydrogen phosphate, sodium-chloride, zinc salts, colloidalsilica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-basedsubstances, polyethylene glycol, sodium carboxymethyl cellulose,polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, andwool fat. Cyclodextrins such as α-, β, and γ-cyclodextrin, or chemicallymodified derivatives such as hydroxyalkylcyclodextrins, including 2- and3-hydroxypropyl-β-cyclodextrins, or other solubilized derivatives canalso be used to enhance delivery of compounds described herein. Dosageforms or compositions containing a chemical entity as described hereinin the range of 0.005% to 100% with the balance made up from non-toxicexcipient may be prepared. The contemplated compositions may contain0.001%400% of a chemical entity provided herein, in one embodiment0.1-95%, in another embodiment 75-85%, in a further embodiment 20-80%.Actual methods of preparing such dosage forms are known, or will beapparent, to those skilled in this art; for example, see Remington: TheScience and Practice of Pharmacy, 22^(nd) Edition (Pharmaceutical Press,London, U K. 2012).

Routes of Administration and Composition Components

In some embodiments, the chemical entities described herein or apharmaceutical composition thereof can be administered to subject inneed thereof by any accepted route of administration. Acceptable routesof administration include, but are not limited to, buccal, cutaneous,endocervical, endosinusial, endotracheal, enteral, epidural,interstitial, intra-abdominal, intra-arterial, intrabronchial,intrabursal, intracerebral, intraci sternal, intracoronary, intradermal,intraductal, intraduodenal, intradural, intraepidermal, intraesophageal,intragastric, intragingival, intraileal, intralymphatic, intramedullary,intrameningeal, intramuscular, intraovarian, intraperitoneal,intraprostatic, intrapulmonary, intrasinal, intraspinal, intrasynovial,intratesticular, intrathecal, intratubular, intratumoral, intrauterine,intravascular, intravenous, nasal, nasogastric, oral, parenteral,percutaneous, peridural, rectal, respiratory (inhalation), subcutaneous,sublingual, submucosal, topical, transdermal, transmucosal,transtracheal, ureteral, urethral and vaginal. In certain embodiments, apreferred route of administration is parenteral (e.g., intratumoral).

Compositions can be formulated for parenteral administration, e.g.,formulated for injection via the intravenous, intramuscular,sub-cutaneous, or even intraperitoneal routes. Typically, suchcompositions can be prepared as injectables, either as liquid solutionsor suspensions; solid forms suitable for use to prepare solutions orsuspensions upon the addition of a liquid prior to injection can also beprepared; and the preparations can also be emulsified. The preparationof such formulations will be known to those of skill in the art in lightof the present disclosure.

The pharmaceutical forms suitable for injectable use include sterileaqueous solutions or dispersions; formulations including sesame oil,peanut oil, or aqueous propylene glycol; and sterile powders for theextemporaneous preparation of sterile injectable solutions ordispersions. In all cases the form must be sterile and must be fluid tothe extent that it may be easily injected. It also should be stableunder the conditions of manufacture and storage and must be preservedagainst the contaminating action of microorganisms, such as bacteria andfungi.

The carrier also can be a solvent or dispersion medium containing, forexample, water, ethanol, polyol (for example, glycerol, propyleneglycol, and liquid polyethylene glycol, and the like), suitable mixturesthereof, and vegetable oils. The proper fluidity can be maintained, forexample, by the use of a coating, such as lecithin, by the maintenanceof the required particle size in the case of dispersion, and by the useof surfactants. The prevention of the action of microorganisms can bebrought about by various antibacterial and antifungal agents, forexample, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, andthe like. In many cases, it will be preferable to include isotonicagents, for example, sugars or sodium chloride. Prolonged absorption ofthe injectable compositions can be brought about by the use in thecompositions of agents delaying absorption, for example, aluminummonostearate and gelatin.

Sterile injectable solutions are prepared by incorporating the activecompounds in the required amount in the appropriate solvent with variousof the other ingredients enumerated above, as required, followed byfiltered sterilization. Generally, dispersions are prepared byincorporating the various sterilized active ingredients into a sterilevehicle which contains the basic dispersion medium and the requiredother ingredients from those enumerated above. In the case of sterilepowders for the preparation of sterile injectable solutions, thepreferred methods of preparation are vacuum-drying and freeze-dryingtechniques, which yield a powder of the active ingredient, plus anyadditional desired ingredient from a previously sterile-filteredsolution thereof.

Intratumoral injections are discussed, e.g., in Lammers, et al., “Effectof Intratumoral Injection on the Biodistribution and the TherapeuticPotential of HPMA Copolymer-Based Drug Delivery Systems” Neoplasia.2006, 10, 788-795.

In certain embodiments, the chemical entities described herein or apharmaceutical composition thereof are suitable for local, topicaladministration to the digestive or GI tract, e.g., rectaladministration. Rectal compositions include, without limitation, enemas,rectal gels, rectal foams, rectal aerosols, suppositories, jellysuppositories, and enemas (e.g., retention enemas).

Pharmacologically acceptable excipients usable in the rectal compositionas a gel, cream, enema, or rectal suppository, include, withoutlimitation, any one or more of cocoa butter glycerides, syntheticpolymers such as polyvinylpyrrolidone, PEG (like PEG ointments),glycerine, glycerinated gelatin, hydrogenated vegetable oils,poloxamers, mixtures of polyethylene glycols of various molecularweights and fatty acid esters of polyethylene glycol Vaseline, anhydrouslanolin, shark liver oil, sodium saccharinate, menthol, sweet almondoil, sorbitol, sodium benzoate, anoxid SBN, vanilla essential oil,aerosol, parabens in phenoxyethanol, sodium methyl p-oxybenzoate, sodiumpropyl p-oxybenzoate, diethylamine, carbomers, carbopol,methyloxybenzoate, macrogol cetostearyl ether, cocoyl caprylocaprate,isopropyl alcohol, propylene glycol, liquid paraffin, xanthan gum,carboxy-metabisulfite, sodium edetate, sodium benzoate, potassiummetabisulfite, grapefruit seed extract, methyl sulfonyl methane (MSM),lactic acid, glycine, vitamins, such as vitamin A and E and potassiumacetate.

In certain embodiments, suppositories can be prepared by mixing thechemical entities described herein with suitable non-irritatingexcipients or carriers such as cocoa butter, polyethylene glycol or asuppository wax which are solid at ambient temperature but liquid atbody temperature and therefore melt in the rectum and release the activecompound. In other embodiments, compositions for rectal administrationare in the form of an enema.

In other embodiments, the compounds described herein or a pharmaceuticalcomposition thereof are suitable for local delivery to the digestive orGI tract by way of oral administration (e.g., solid or liquid dosageforms.).

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the chemicalentity is mixed with one or more pharmaceutically acceptable excipients,such as sodium citrate or dicalcium phosphate and/or: a) fillers orextenders such as starches, lactose, sucrose, glucose, mannitol, andsilicic acid, b) binders such as, for example, carboxymethylcellulose,alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c)humectants such as glycerol, d) disintegrating agents such as agar-agar,calcium carbonate, potato or tapioca starch, alginic acid, certainsilicates, and sodium carbonate, e) solution retarding agents such asparaffin, f) absorption accelerators such as quaternary ammoniumcompounds, g) wetting agents such as, for example, cetyl alcohol andglycerol monostearate, h) absorbents such as kaolin and bentonite clay,and i) lubricants such as talc, calcium stearate, magnesium stearate,solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof.In the case of capsules, tablets and pills, the dosage form may alsocomprise buffering agents. Solid compositions of a similar type may alsobe employed as fillers in soft and hard-filled gelatin capsules usingsuch excipients as lactose or milk sugar as well as high molecularweight polyethylene glycols and the like.

In one embodiment, the compositions will take the form of a unit dosageform such as a pill or tablet and thus the composition may contain,along with a chemical entity provided herein, a diluent such as lactose,sucrose, dicalcium phosphate, or the like; a lubricant such as magnesiumstearate or the like; and a binder such as starch, gum acacia,polyvinylpyrrolidine, gelatin, cellulose, cellulose derivatives or thelike. In another solid dosage form, a powder, marume, solution orsuspension (e.g., in propylene carbonate, vegetable oils, PEG's,poloxamer 124 or triglycerides) is encapsulated in a capsule (gelatin orcellulose base capsule). Unit dosage forms in which one or more chemicalentities provided herein or additional active agents are physicallyseparated are also contemplated; e.g., capsules with granules (ortablets in a capsule) of each drug; two-layer tablets; two-compartmentgel caps, etc. Enteric coated or delayed release oral dosage forms arealso contemplated.

Other physiologically acceptable compounds include wetting agents,emulsifying agents, dispersing agents or preservatives that areparticularly useful for preventing the growth or action ofmicroorganisms. Various preservatives are well known and include, forexample, phenol and ascorbic acid.

In certain embodiments the excipients are sterile and generally free ofundesirable matter. These compositions can be sterilized byconventional, well-known sterilization techniques. For various oraldosage form excipients such as tablets and capsules sterility is notrequired. The USP/NF standard is usually sufficient.

In certain embodiments, solid oral dosage forms can further include oneor more components that chemically and/or structurally predispose thecomposition for delivery of the chemical entity to the stomach or thelower GI; e.g., the ascending colon and/or transverse colon and/ordistal colon and/or small bowel. Exemplary formulation techniques aredescribed in, e.g., Filipski, K. J., et al., Current Topics in MedicinalChemistry, 2013, 13, 776-802, which is incorporated herein by referencein its entirety.

Examples include upper-GI targeting techniques, e.g., Accordion Pill(Intec Pharma), floating capsules, and materials capable of adhering tomucosal walls.

Other examples include lower-GI targeting techniques. For targetingvarious regions in the intestinal tract, several enteric/pH-responsivecoatings and excipients are available. These materials are typicallypolymers that are designed to dissolve or erode at specific pH ranges,selected based upon the GI region of desired drug release. Thesematerials also function to protect acid labile drugs from gastric fluidor limit exposure in cases where the active ingredient may be irritatingto the upper GI (e.g., hydroxypropyl methylcellulose phthalate series,Coateric (polyvinyl acetate phthalate), cellulose acetate phthalate,hydroxypropyl methylcellulose acetate succinate, Eudragit series(methacrylic acid-methyl methacrylate copolymers), and Marcoat). Othertechniques include dosage forms that respond to local flora in the GItract, Pressure-controlled colon delivery capsule, and Pulsincap.

Ocular compositions can include, without limitation, one or more of anyof the following: viscogens (e.g., Carboxymethylcellulose, Glycerin,Polyvinylpyrrolidone, Polyethylene glycol); Stabilizers (e.g., Pluronic(triblock copolymers), Cyclodextrins); Preservatives (e.g., Benzalkoniumchloride, ETDA, SofZia (boric acid, propylene glycol, sorbitol, and zincchloride; Alcon Laboratories, Inc.), Purite (stabilized oxychlorocomplex; Allergan, Inc.)).

Topical compositions can include ointments and creams. Ointments aresemisolid preparations that are typically based on petrolatum or otherpetroleum derivatives. Creams containing the selected active agent aretypically viscous liquid or semisolid emulsions, often eitheroil-in-water or water-in-oil. Cream bases are typically water-washable,and contain an oil phase, an emulsifier and an aqueous phase. The oilphase, also sometimes called the “internal” phase, is generallycomprised of petrolatum and a fatty alcohol such as cetyl or stearylalcohol; the aqueous phase usually, although not necessarily, exceedsthe oil phase in volume, and generally contains a humectant. Theemulsifier in a cream formulation is generally a nonionic, anionic,cationic or amphoteric surfactant. As with other carriers or vehicles,an ointment base should be inert, stable, nonirritating andnon-sensitizing.

In any of the foregoing embodiments, pharmaceutical compositionsdescribed herein can include one or more one or more of the following:lipids, interbilayer crosslinked multilamellar vesicles, biodegradeablepoly(D,L-lactic-co-glycolic acid) [PLGA]-based or poly anhydride-basednanoparticles or microparticles, and nanoporous particle-supported lipidbilayers.

Enema Formulations

In some embodiments, enema formulations containing the chemical entitiesdescribed herein are provided in “ready-to-use” form.

In some embodiments, enema formulations containing the chemical entitiesdescribed herein are provided in one or more kits or packs. In certainembodiments, the kit or pack includes two or more separatelycontained/packaged components, e.g. two components, which when mixedtogether, provide the desired formulation (e.g., as a suspension). Incertain of these embodiments, the two component system includes a firstcomponent and a second component, in which: (i) the first component(e.g., contained in a sachet) includes the chemical entity (as describedanywhere herein) and optionally one or more pharmaceutically acceptableexcipients (e.g., together formulated as a solid preparation, e.g.,together formulated as a wet granulated solid preparation); and (ii) thesecond component (e.g., contained in a vial or bottle) includes one ormore liquids and optionally one or more other pharmaceuticallyacceptable excipients together forming a liquid carrier. Prior to use(e.g., immediately prior to use), the contents of (i) and (ii) arecombined to form the desired enema formulation, e.g., as a suspension.In other embodiments, each of component (i) and (ii) is provided in itsown separate kit or pack.

In some embodiments, each of the one or more liquids is water, or aphysiologically acceptable solvent, or a mixture of water and one ormore physiologically acceptable solvents. Typical such solvents include,without limitation, glycerol, ethylene glycol, propylene glycol,polyethylene glycol and polypropylene glycol. In certain embodiments,each of the one or more liquids is water. In other embodiments, each ofthe one or more liquids is an oil, e.g. natural and/or synthetic oilsthat are commonly used in pharmaceutical preparations.

Further pharmaceutical excipients and carriers that may be used in thepharmaceutical products herein described are listed in various handbooks(e.g. D. E. Bugay and W. P. Findlay (Eds) Pharmaceutical excipients(Marcel Dekker, New York, 1999), E-M Hoepfner, A. Reng and P. C. Schmidt(Eds) Fiedler Encyclopedia of Excipients for Pharmaceuticals, Cosmeticsand Related Areas (Edition Cantor, Munich, 2002) and H. P. Fielder (Ed)Lexikon der Hilfsstoffe fur Pharmazie, Kosmetik and angrenzende Gebiete(Edition Cantor Aulendorf, 1989)).

In some embodiments, each of the one or more pharmaceutically acceptableexcipients can be independently selelcted from thickeners, viscosityenhancing agents, bulking agents, mucoadhesive agents, penetrationenhanceers, buffers, preservatives, diluents, binders, lubricants,glidants, disintegrants, fillers, solubilizing agents, pH modifyingagents, preservatives, stabilizing agents, anti-oxidants, wetting oremulsifying agents, suspending agents, pigments, colorants, isotonicagents, chelating agents, emulsifiers, and diagnostic agents.

In certain embodiments, each of the one or more pharmaceuticallyacceptable excipients can be independently selelcted from thickeners,viscosity enhancing agents, mucoadhesive agents, buffers, preservatives,diluents, binders, lubricants, glidants, disintegrants, and fillers.

In certain embodiments, each of the one or more pharmaceuticallyacceptable excipients can be independently selelcted from thickeners,viscosity enhancing agents, bulking agents, mucoadhesive agents,buffers, preservatives, and fillers.

In certain embodiments, each of the one or more pharmaceuticallyacceptable excipients can be independently selelcted from diluents,binders, lubricants, glidants, and disintegrants.

Examples of thickeners, viscosity enhancing agents, and mucoadhesiveagents include without limitation: gums, e.g. xanthan gum, guar gum,locust bean gum, tragacanth gums, karaya gum, ghatti gum, cholla gum,psyllium seed gum and gum arabic; poly(carboxylic acid-containing) basedpolymers, such as poly (acrylic, maleic, itaconic, citraconic,hydroxyethyl methacrylic or methacrylic) acid which have stronghydrogen-bonding groups, or derivatives thereof such as salts andesters; cellulose derivatives, such as methyl cellulose, ethylcellulose, methylethyl cellulose, hydroxymethyl cellulose, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxyethyl ethyl cellulose,carboxymethyl cellulose, hydroxypropylmethyl cellulose or celluloseesters or ethers or derivatives or salts thereof; clays such asmanomorillonite clays, e.g. Veegun, attapulgite clay; polysaccharidessuch as dextran, pectin, amylopectin, agar, mannan or polygalactonicacid or starches such as hydroxypropyl starch or carboxymethyl starch;polypeptides such as casein, gluten, gelatin, fibrin glue; chitosan,e.g. lactate or glutamate or carboxymethyl chitin; glycosaminoglycanssuch as hyaluronic acid; metals or water soluble salts of alginic acidsuch as sodium alginate or magnesium alginate; schleroglucan; adhesivescontaining bismuth oxide or aluminium oxide; atherocollagen; polyvinylpolymers such as carboxyvinyl polymers; polyvinylpyrrolidone (povidone);polyvinyl alcohol; polyvinyl acetates, polyvinylmethyl ethers, polyvinylchlorides, polyvinylidenes, and/or the like; polycarboxylated vinylpolymers such as polyacrylic acid as mentioned above; polysiloxanes;polyethers; polyethylene oxides and glycols; polyalkoxys andpolyacrylamides and derivatives and salts thereof. Preferred examplescan include cellulose derivatives, such as methyl cellulose, ethylcellulose, methylethyl cellulose, hydroxymethyl cellulose, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxyethyl ethyl cellulose,carboxymethyl cellulose, hydroxypropylmethyl cellulose or celluloseesters or ethers or derivatives or salts thereof (e.g., methylcellulose); and polyvinyl polymers such as polyvinylpyrrolidone(povidone).

Examples of preservatives include without limitation: benzalkoniumchloride, benzoxonium chloride, benzethonium chloride, cetrimide,sepazonium chloride, cetylpyridinium chloride, domiphen bromide(Bradosol®), thiomersal, phenylmercuric nitrate, phenylmercuric acetate,phenylmercuric borate, methylparaben, propylparaben, chlorobutanol,benzyl alcohol, phenyl ethyl alcohol, chlorohexidine, polyhexamethylenebiguanide, sodium perborate, imidazolidinyl urea, sorbic acid, Purite®),Polyquart®), and sodium perborate tetrahydrate and the like.

In certain embodiments, the preservative is a paraben, or apharmaceutically acceptable salt thereof. In some embodiments, theparaben is an alkyl substituted 4-hydroxybenzoate, or a pharmaceuticallyacceptable salt or ester thereof. In certain embodiments, the alkyl is aC1-C4 alkyl. In certain embodiments, the preservative is methyl4-hydroxybenzoate (methylparaben), or a pharmaceutically acceptable saltor ester thereof, propyl 4-hydroxybenzoate (propylparaben), or apharmaceutically acceptable salt or ester thereof, or a combinationthereof.

Examples of buffers include without limitation: phosphate buffer system(sodium dihydrogen phospahate dehydrate, disodium phosphatedodecahydrate, bibasic sodium phosphate, anhydrous monobasic sodiumphosphate), bicarbonate buffer system, and bisulfate buffer system.

Examples of disintegrants include, without limitation: carmellosecalcium, low substituted hydroxypropyl cellulose (L-HPC), carmellose,croscarmellose sodium, partially pregelatinized starch, dry starch,carboxymethyl starch sodium, crospovidone, polysorbate 80(polyoxyethylenesorbitan oleate), starch, sodium starch glycolate,hydroxypropyl cellulose pregelatinized starch, clays, cellulose,alginine, gums or cross linked polymers, such as crosslinked PVP(Polyplasdone XL from GAF Chemical Corp). In certain embodiments, thedisintegrant is crospovidone.

Examples of glidants and lubricants (aggregation inhibitors) includewithout limitation: talc, magnesium stearate, calcium stearate,colloidal silica, stearic acid, aqueous silicon dioxide, syntheticmagnesium silicate, fine granulated silicon oxide, starch, sodiumlaurylsulfate, boric acid, magnesium oxide, waxes, hydrogenated oil,polyethylene glycol, sodium benzoate, stearic acid glycerol behenate,polyethylene glycol, and mineral oil. In certain embodiments, theglidant/lubricant is magnesium stearate, talc, and/or colloidal silica;e.g., magnesium stearate and/or talc.

Examples of diluents, also referred to as “fillers” or “bulking agents”include without limitation: dicalcium phosphate dihydrate, calciumsulfate, lactose (e.g., lactose monohydrate), sucrose, mannitol,sorbitol, cellulose, microcrystalline cellulose, kaolin, sodiumchloride, dry starch, hydrolyzed starches, pregelatinized starch,silicone dioxide, titanium oxide, magnesium aluminum silicate andpowdered sugar. In certain embodiments, the diluent is lactose (e.g.,lactose monohydrate).

Examples of binders include without limitation: starch, pregelatinizedstarch, gelatin, sugars (including sucrose, glucose, dxtrose, lactoseand sorbitol), polyethylene glycol, waxes, natural and synthetic gumssuch as acacia tragacanth, sodium alginate cellulose, includinghydroxypropylmethylcellulose, hydroxypropylcellulose, ethylcellulose,and veegum, and synthetic polymers such as acrylic acid and methacrylicacid copolymers, methacrylic acid copolymers, methyl methacrylatecopolymers, aminoalkyl methacrylate copolymers, polyacrylicacid/polymethacrylic acid and polyvinylpyrrolidone (povidone). Incertain embodiments, the binder is polyvinylpyrrolidone (povidone).

In some embodiments, enema formulations containing the chemical entitiesdescribed herein include water and one or more (e.g., all) of thefollowing excipients:

-   -   One or more (e.g., one, two, or three) thickeners, viscosity        enhancing agents, binders, and/or mucoadhesive agents (e.g.,        cellulose or cellulose esters or ethers or derivatives or salts        thereof (e.g., methyl cellulose); and polyvinyl polymers such as        polyvinylpyrrolidone (povidone);    -   One or more (e.g., one or two; e.g., two) preservatives, such as        a paraben, e.g., methyl 4-hydroxybenzoate (methylparaben), or a        pharmaceutically acceptable salt or ester thereof, propyl        4-hydroxybenzoate (propylparaben), or a pharmaceutically        acceptable salt or ester thereof, or a combination thereof;    -   One or more (e.g., one or two; e.g., two) buffers, such as        phosphate buffer system (e.g., sodium dihydrogen phospahate        dehydrate, disodium phosphate dodecahydrate);    -   One or more (e.g., one or two, e.g., two) glidants and/or        lubricants, such as magnesium stearate and/or talc;    -   One or more (e.g., one or two; e.g., one) disintegrants, such as        crospovidone; and    -   One or more (e.g., one or two; e.g., one) diluents, such as        lactose (e.g., lactose monohydrate).

In certain of these embodiments, the chemical entity is a compound ofFormula AA, or a pharmaceutically acceptable salt and/or hydrate and/orcocrystal thereof.

In certain embodiments, enema formulations containing the chemicalentities described herein include water, methyl cellulose, povidone,methylparaben, propylparaben, sodium dihydrogen phospahate dehydrate,disodium phosphate dodecahydrate, crospovidone, lactose monohydrate,magnesium stearate, and talc. In certain of these embodiments, thechemical entity is a compound of Formula AA, or a pharmaceuticallyacceptable salt and/or hydrate and/or cocrystal thereof.

In certain embodiments, enema formulations containing the chemicalentities described herein are provided in one or more kits or packs. Incertain embodiments, the kit or pack includes two separatelycontained/packaged components, which when mixed together, provide thedesired formulation (e.g., as a suspension). In certain of theseembodiments, the two component system includes a first component and asecond component, in which: (i) the first component (e.g., contained ina sachet) includes the chemical entity (as described anywhere herein)and one or more pharmaceutically acceptable excipients (e.g., togetherformulated as a solid preparation, e.g., together formulated as a wetgranulated solid preparation); and (ii) the second component (e.g.,contained in a vial or bottle) includes one or more liquids and one ormore one or more other pharmaceutically acceptable excipients togetherforming a liquid carrier. In other embodiments, each of component (i)and (ii) is provided in its own separate kit or pack.

In certain of these embodiments, component (i) includes the chemicalentitiy (e.g., a compound of Formula AA, or a pharmaceuticallyacceptable salt and/or hydrate and/or cocrystal thereof; e.g., acompound of Formula AA) and one or more (e.g., all) of the followingexcipients:

-   -   (a) One or more (e.g., one) binders (e.g., a polyvinyl polymer,        such as polyvinylpyrrolidone (povidone);    -   (b) One or more (e.g., one or two, e.g., two) glidants and/or        lubricants, such as magnesium stearate and/or talc;    -   (c) One or more (e.g., one or two; e.g., one) disintegrants,        such as crospovidone; and    -   (d) One or more (e.g., one or two; e.g., one) diluents, such as        lactose (e.g., lactose monohydrate).

In certain embodiments, component (i) includes from about 40 weightpercent to about 80 weight percent (e.g., from about 50 weight percentto about 70 weight percent, from about 55 weight percent to about 70weight percent; from about 60 weight percent to about 65 weight percent;e.g., about 62.1 weight percent) of the chemical entity (e.g., acompound of Formula AA, or a pharmaceutically acceptable salt and/orhydrate and/or cocrystal thereof).

In certain embodiments, component (i) includes from about 0.5 weightpercent to about 5 weight percent (e.g., from about 1.5 weight percentto about 4.5 weight percent, from about 2 weight percent to about 3.5weight percent; e.g., about 2.76 weight percent) of the binder (e.g.,povidone).

In certain embodiments, component (i) includes from about 0.5 weightpercent to about 5 weight percent (e.g., from about 0.5 weight percentto about 3 weight percent, from about 1 weight percent to about 3 weightpercent; about 2 weight percent e.g., about 1.9 weight percent) of thedisintegrant (e.g., crospovidone).

In certain embodiments, component (i) includes from about 10 weightpercent to about 50 weight percent (e.g., from about 20 weight percentto about 40 weight percent, from about 25 weight percent to about 35weight percent; e.g., about 31.03 weight percent) of the diluent (e.g.,lactose, e.g., lactose monohydrate).

In certain embodiments, component (i) includes from about 0.05 weightpercent to about 5 weight percent (e.g., from about 0.05 weight percentto about 3 weight percent) of the glidants and/or lubricants.

In certain embodiments (e.g., when component (i) includes one or morelubricants, such as magnesium stearate), component (i) includes fromabout 0.05 weight percent to about 1 weight percent (e.g., from about0.05 weight percent to about 1 weight percent; from about 0.1 weightpercent to about 1 weight percent; from about 0.1 weight percent toabout 0.5 weight percent; e.g., about 0.27 weight percent) of thelubricant (e.g., magnesium stearate).

In certain embodiments (when component (i) includes one or morelubricants, such as talc), component (i) includes from about 0.5 weightpercent to about 5 weight percent (e.g., from about 0.5 weight percentto about 3 weight percent, from about 1 weight percent to about 3 weightpercent; from about 1.5 weight percent to about 2.5 weight percent; fromabout 1.8 weight percent to about 2.2 weight percent; about 1.93 weightpercent) of the lubricant (e.g., talc).

In certain of these embodiments, each of (a), (b), (c), and (d) above ispresent.

In certain embodiments, component (i) includes the ingredients andamounts as shown in Table A.

TABLE A Ingredient Weight Percent A compound of 40 weight percent toabout 80 weight Formula AA percent (e.g., from about 50 weight percentto about 70 weight percent, from about 55 weight percent to about 70weight percent; from about 60 weight percent to about 65 weight percent;e.g., about 62.1 weight percent) Crospovidone 0.5 weight percent toabout 5 weight (Kollidon CL) percent (e.g., from about 0.5 weightpercent to about 3 weight percent, from about 1 weight percent to about3 weight percent; about 1.93 weight percent lactose monohydrate about 10weight percent to about 50 weight (Pharmatose 200M) percent (e.g., fromabout 20 weight percent to about 40 weight percent, from about 25 weightpercent to about 35 weight percent; e.g., about 31.03 weight percentPovidone (Kollidon about 0.5 weight percent to about 5 weight K30)percent (e.g., from about 1.5 weight percent to about 4.5 weightpercent, from about 2 weight percent to about 3.5 weight percent; e.g.,about 2.76 weight percent talc 0.5 weight percent to about 5 weightpercent (e.g., from about 0.5 weight percent to about 3 weight percent,from about 1 weight percent to about 3 weight percent; from about 1.5weight percent to about 2.5 weight percent; from about 1.8 weightpercent to about 2.2 weight percent; e.g., about 1.93 weight percentMagnesium stearate about 0.05 weight percent to about 1 weight percent(e.g., from about 0.05 weight percent to about 1 weight percent; fromabout 0.1 weight percent to about 1 weight percent; from about 0.1weight percent to about 0.5 weight percent; e.g., about 0.27 weightpercent

In certain embodiments, component (i) includes the ingredients andamounts as shown in Table B.

TABLE B Ingredient Weight Percent A compound of Formula AA About 62.1weight percent) Crospovidone (Kollidon CL) About 1.93 weight percentlactose monohydrate (Pharmatose 200M) About 31.03 weight percentPovidone (Kollidon K30) About 2.76 weight percent talc About 1.93 weightpercent Magnesium stearate About 0.27 weight percent

In certain embodiments, component (i) is formulated as a wet granulatedsolid preparation. In certain of these embodiments an internal phase ofingredients (the chemical entity, disintegrant, and diluent) arecombined and mixed in a high-shear granulator. A binder (e.g., povidone)is dissolved in water to form a granulating solution. This solution isadded to the Inner Phase mixture resulting in the development ofgranules. While not wishing to be bound by theory, granule developmentis believed to be facilitated by the interaction of the polymeric binderwith the materials of the internal phase. Once the granulation is formedand dried, an external phase (e.g., one or more lubricants—not anintrinsic component of the dried granulation), is added to the drygranulation. It is believed that lubrication of the granulation isimportant to the flowability of the granulation, in particular forpackaging.

In certain of the foregoing embodiments, component (ii) includes waterand one or more (e.g., all) of the following excipients:

-   -   (a′) One or more (e.g., one, two; e.g., two) thickeners,        viscosity enhancing agents, binders, and/or mucoadhesive agents        (e.g., cellulose or cellulose esters or ethers or derivatives or        salts thereof (e.g., methyl cellulose); and polyvinyl polymers        such as polyvinylpyrrolidone (povidone);    -   (b′) One or more (e.g., one or two; e.g., two) preservatives,        such as a paraben, e.g., methyl 4-hydroxybenzoate        (methylparaben), or a pharmaceutically acceptable salt or ester        thereof, propyl 4-hydroxybenzoate (propylparaben), or a        pharmaceutically acceptable salt or ester thereof, or a        combination thereof; and    -   (c′) One or more (e.g., one or two; e.g., two) buffers, such as        phosphate buffer system (e.g., sodium dihydrogen phospahate        dihydrate, disodium phosphate dodecahydrate);

In certain of the foregoing embodiments, component (ii) includes waterand one or more (e.g., all) of the following excipients:

-   -   (a″) a first thickener, viscosity enhancing agent, binder,        and/or mucoadhesive agent (e.g., a cellulose or cellulose ester        or ether or derivative or salt thereof (e.g., methyl        cellulose));    -   (a′) a second thickener, viscosity enhancing agent, binder,        and/or mucoadhesive agent (e.g., a polyvinyl polymer, such as        polyvinylpyrrolidone (povidone));    -   (b″) a first preservative, such as a paraben, e.g., propyl        4-hydroxybenzoate    -   (propylparaben), or a pharmaceutically acceptable salt or ester        thereof;    -   (b″) a second preservative, such as a paraben, e.g., methyl        4-hydroxybenzoate    -   (methylparaben), or a pharmaceutically acceptable salt or ester        thereof,    -   (c″) a first buffer, such as phosphate buffer system (e.g.,        disodium phosphate dodecahydrate);    -   (c′″) a second buffer, such as phosphate buffer system (e.g.,        sodium dihydrogen phospahate dehydrate),

In certain embodiments, component (ii) includes from about 0.05 weightpercent to about 5 weight percent (e.g., from about 0.05 weight percentto about 3 weight percent, from about 0.1 weight percent to about 3weight percent; e.g., about 1.4 weight percent) of (a″).

In certain embodiments, component (ii) includes from about 0.05 weightpercent to about 5 weight percent (e.g., from about 0.05 weight percentto about 3 weight percent, from about 0.1 weight percent to about 2weight percent; e.g., about 1.0 weight percent) of (a′″).

In certain embodiments, component (ii) includes from about 0.005 weightpercent to about 0.1 weight percent (e.g., from about 0.005 weightpercent to about 0.05 weight percent; e.g., about 0.02 weight percent)of (b″).

In certain embodiments, component (ii) includes from about 0.05 weightpercent to about 1 weight percent (e.g., from about 0.05 weight percentto about 0.5 weight percent; e.g., about 0.20 weight percent) of (b′″).

In certain embodiments, component (ii) includes from about 0.05 weightpercent to about 1 weight percent (e.g., from about 0.05 weight percentto about 0.5 weight percent; e.g., about 0.15 weight percent) of (c″).

In certain embodiments, component (ii) includes from about 0.005 weightpercent to about 0.5 weight percent (e.g., from about 0.005 weightpercent to about 0.3 weight percent; e.g., about 0.15 weight percent) of(c′″).

In certain of these embodiments, each of (a″)-(c′) is present.

In certain embodiments, component (ii) includes water (up to 100%) andthe ingredients and amounts as shown in Table C.

TABLE C Ingredient Weight Percent methyl cellulose 0.05 weight percentto about 5 weight (Methocel A15C percent (e.g., from about 0.05 weightpremium) percent to about 3 weight percent, from about 0.1 weightpercent to about 3 weight percent; e.g., about 1.4 weight percentPovidone (Kollidon 0.05 weight percent to about 5 weight K30) percent(e.g., from about 0.05 weight percent to about 3 weight percent, fromabout 0.1 weight percent to about 2 weight percent; e.g., about 1.0weight percent propyl 4- about 0.005 weight percent to about 0.1hydroxybenzoate weight percent (e.g., from about 0.005 weight percent toabout 0.05 weight percent; e.g., about 0.02 weight percent) methyl 4-about 0.05 weight percent to about 1 hydroxybenzoate weight percent(e.g., from about 0.05 weight percent to about 0.5 weight percent; e.g.,about 0.20 weight percent) disodium phosphate about 0.05 weight percentto about 1 dodecahydrate weight percent (e.g., from about 0.05 weightpercent to about 0.5 weight percent; e.g., about 0.15 weight percent)sodium dihydrogen about 0.005 weight percent to about 0.5 phospahatedihydrate weight percent (e.g., from about 0.005 weight percent to about0.3 weight percent; e.g., about 0.15 weight percent)

In certain embodiments, component (ii) includes water (up to 100%) andthe ingredients and amounts as shown in Table D.

TABLE D Ingredient Weight Percent methyl cellulose (Methocel A15Cpremium) about 1.4 weight percent Povidone (Kollidon K30) about 1.0weight percent propyl 4-hydroxybenzoate about 0.02 weight percent methyl4-hydroxybenzoate about 0.20 weight percent disodium phosphatedodecahydrate about 0.15 weight percent sodium dihydrogen phospahatedihydrate about 0.15 weight percent

Ready-to-use” enemas are generally be provided in a “single-use” sealeddisposable container of plastic or glass. Those formed of a polymericmaterial preferably have sufficient flexibility for ease of use by anunassisted patient. Typical plastic containers can be made ofpolyethylene. These containers may comprise a tip for directintroduction into the rectum. Such containers may also comprise a tubebetween the container and the tip. The tip is preferably provided with aprotective shield which is removed before use. Optionally the tip has alubricant to improve patient compliance.

In some embodiments, the enema formulation (e.g., suspension) is pouredinto a bottle for delivery after it has been prepared in a separatecontainer. In certain embodiments, the bottle is a plastic bottle (e.g.,flexible to allow for delivery by squeezing the bottle), which can be apolyethylene bottle (e.g., white in color). In some embodiments, thebottle is a single chamber bottle, which contains the suspension orsolution. In other embodiments, the bottle is a multichamber bottle,where each chamber contains a separate mixture or solution. In stillother embodiments, the bottle can further include a tip or rectalcannula for direct introduction into the rectum. In some embodiments,the enema formulation can be delivered in the device shown in FIGS.3A-3C, which includes a plastic bottle, a breakable capsule, and arectal cannula and single flow pack.

Dosages

The dosages may be varied depending on the requirement of the patient,the severity of the condition being treating and the particular compoundbeing employed. Determination of the proper dosage for a particularsituation can be determined by one skilled in the medical arts. Thetotal daily dosage may be divided and administered in portionsthroughout the day or by means providing continuous delivery.

In some embodiments, the compounds described herein are administered ata dosage of from about 0.001 mg/Kg to about 500 mg/Kg (e.g., from about0.001 mg/Kg to about 200 mg/Kg; from about 0.01 mg/Kg to about 200mg/Kg; from about 0.01 mg/Kg to about 150 mg/Kg; from about 0.01 mg/Kgto about 100 mg/Kg; from about 0.01 mg/Kg to about 50 mg/Kg; from about0.01 mg/Kg to about 10 mg/Kg; from about 0.01 mg/Kg to about 5 mg/Kg;from about 0.01 mg/Kg to about 1 mg/Kg; from about 0.01 mg/Kg to about0.5 mg/Kg; from about 0.01 mg/Kg to about 0.1 mg/Kg; from about 0.1mg/Kg to about 200 mg/Kg; from about 0.1 mg/Kg to about 150 mg/Kg; fromabout 0.1 mg/Kg to about 100 mg/Kg; from about 0.1 mg/Kg to about 50mg/Kg; from about 0.1 mg/Kg to about 10 mg/Kg; from about 0.1 mg/Kg toabout 5 mg/Kg; from about 0.1 mg/Kg to about 1 mg/Kg; from about 0.1mg/Kg to about 0.5 mg/Kg).

In some embodiments, enema formulations include from about 0.5 mg toabout 2500 mg (e.g., from about 0.5 mg to about 2000 mg, from about 0.5mg to about 1000 mg, from about 0.5 mg to about 750 mg, from about 0.5mg to about 600 mg, from about 0.5 mg to about 500 mg, from about 0.5 mgto about 400 mg, from about 0.5 mg to about 300 mg, from about 0.5 mg toabout 200 mg; e.g., from about 5 mg to about 2500 mg, from about 5 mg toabout 2000 mg, from about 5 mg to about 1000 mg; from about 5 mg toabout 750 mg; from about 5 mg to about 600 mg; from about 5 mg to about500 mg; from about 5 mg to about 400 mg; from about 5 mg to about 300mg; from about 5 mg to about 200 mg; e.g., from about 50 mg to about2000 mg, from about 50 mg to about 1000 mg, from about 50 mg to about750 mg, from about 50 mg to about 600 mg, from about 50 mg to about 500mg, from about 50 mg to about 400 mg, from about 50 mg to about 300 mg,from about 50 mg to about 200 mg; e.g., from about 100 mg to about 2500mg, from about 100 mg to about 2000 mg, from about 100 mg to about 1000mg, from about 100 mg to about 750 mg, from about 100 mg to about 700mg, from about 100 mg to about 600 mg, from about 100 mg to about 500mg, from about 100 mg to about 400 mg, from about 100 mg to about 300mg, from about 100 mg to about 200 mg; e.g., from about 150 mg to about2500 mg, from about 150 mg to about 2000 mg, from about 150 mg to about1000 mg, from about 150 mg to about 750 mg, from about 150 mg to about700 mg, from about 150 mg to about 600 mg, from about 150 mg to about500 mg, from about 150 mg to about 400 mg, from about 150 mg to about300 mg, from about 150 mg to about 200 mg; e.g., from about 150 mg toabout 500 mg; e.g., from about 300 mg to about 2500 mg, from about 300mg to about 2000 mg, from about 300 mg to about 1000 mg, from about 300mg to about 750 mg, from about 300 mg to about 700 mg, from about 300 mgto about 600 mg; e.g., from about 400 mg to about 2500 mg, from about400 mg to about 2000 mg, from about 400 mg to about 1000 mg, from about400 mg to about 750 mg, from about 400 mg to about 700 mg, from about400 mg to about 600 from about 400 mg to about 500 mg; e.g., 150 mg or450 mg) of the chemical entity in from about 1 mL to about 3000 mL(e.g., from about 1 mL to about 2000 mL, from about 1 mL to about 1000mL, from about 1 mL to about 500 mL, from about 1 mL to about 250 mL,from about 1 mL to about 100 mL, from about 10 mL to about 1000 mL, fromabout 10 mL to about 500 mL, from about 10 mL to about 250 mL, fromabout 10 mL to about 100 mL, from about 30 mL to about 90 mL, from about40 mL to about 80 mL; from about 50 mL to about 70 mL; e.g., about 1 mL,about 5 mL, about 10 mL, about 15 mL, about 20 mL, about 25 mL, about 30mL, about 35 mL, about 40 mL, about 45 mL, about 50 mL, about 55 mL,about 60 mL, about 65 mL, about 70 mL, about 75 mL, about 100 mL, about250 mL, or about 500 mL, or about 1000 mL, or about 2000 mL, or about3000 mL; e.g., 60 mL) of liquid carrier.

In certain embodiments, enema formulations include from about 50 mg toabout 250 mg (e.g., from about 100 mg to about 200; e.g., about 150 mg)of the chemical entity in from about 10 mL to about 100 mL (e.g., fromabout 20 mL to about 100 mL, from about 30 mL to about 90 mL, from about40 mL to about 80 mL; from about 50 mL to about 70 mL) of liquidcarrier. In certain embodiments, enema formulations include about 150 mgof the chemical entity in about 60 mL of the liquid carrier. In certainof these embodiments, the chemical entity is a compound of Formula AA,or a pharmaceutically acceptable salt and/or hydrate and/or cocrystalthereof. For example, enema formulations can include about 150 mg of acompound of Formula AA in about 60 mL of the liquid carrier.

In certain embodiments, enema formulations include from about 350 mg toabout 550 mg (e.g., from about 400 mg to about 500; e.g., about 450 mg)of the chemical entity in from about 10 mL to about 100 mL (e.g., fromabout 20 mL to about 100 mL, from about 30 mL to about 90 mL, from about40 mL to about 80 mL; from about 50 mL to about 70 mL) of liquidcarrier. In certain embodiments, enema formulations include about 450 mgof the chemical entity in about 60 mL of the liquid carrier. In certainof these embodiments, the chemical entity is a compound of Formula AA,or a pharmaceutically acceptable salt and/or hydrate and/or cocrystalthereof. For example, enema formulations can include about 450 mg of acompound of Formula AA in about 60 mL of the liquid carrier.

In some embodiments, enema formulations include from about from about0.01 mg/mL to about 50 mg/mL (e.g., from about 0.01 mg/mL to about 25mg/mL; from about 0.01 mg/mL to about 10 mg/mL; from about 0.01 mg/mL toabout 5 mg/mL; from about 0.1 mg/mL to about 50 mg/mL; from about 0.01mg/mL to about 25 mg/mL; from about 0.1 mg/mL to about 10 mg/mL; fromabout 0.1 mg/mL to about 5 mg/mL; from about 1 mg/mL to about 10 mg/mL;from about 1 mg/mL to about 5 mg/mL; from about 5 mg/mL to about 10mg/mL; e.g., about 2.5 mg/mL or about 7.5 mg/mL) of the chemical entityin liquid carrier. In certain of these embodiments, the chemical entityis a compound of Formula AA, or a pharmaceutically acceptable saltand/or hydrate and/or cocrystal thereof. For example, enema formulationscan include about 2.5 mg/mL or about 7.5 mg/mL of a compound of FormulaAA in liquid carrier.

Regimens

The foregoing dosages can be administered on a daily basis (e.g., as asingle dose or as two or more divided doses) or non-daily basis (e.g.,every other day, every two days, every three days, once weekly, twiceweeks, once every two weeks, once a month).

In some embodiments, the period of administration of a compounddescribed herein is for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks,11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9months, 10 months, 11 months, 12 months, or more. In a furtherembodiment, a period of during which administration is stopped is for 1day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11months, 12 months, or more. In an embodiment, a therapeutic compound isadministered to an individual for a period of time followed by aseparate period of time. In another embodiment, a therapeutic compoundis administered for a first period and a second period following thefirst period, with administration stopped during the second period,followed by a third period where administration of the therapeuticcompound is started and then a fourth period following the third periodwhere administration is stopped. In an aspect of this embodiment, theperiod of administration of a therapeutic compound followed by a periodwhere administration is stopped is repeated for a determined orundetermined period of time. In a further embodiment, a period ofadministration is for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks,11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9months, 10 months, 11 months, 12 months, or more. In a furtherembodiment, a period of during which administration is stopped is for 1day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11months, 12 months, or more.

Methods of Treatment

In some embodiments, methods for treating a subject having condition,disease or disorder in which a decrease or increase in NLRP3 activity(e.g., an increase, e.g., NLRP3 signaling) contributes to the pathologyand/or symptoms and/or progression of the condition, disease or disorderare provided, comprising administering to a subject an effective amountof a chemical entity described herein (e.g., a compound describedgenerically or specifically herein or a pharmaceutically acceptable saltthereof or compositions containing the same).

Indications

In some embodiments, the condition, disease or disorder is selectedfrom: inappropriate host responses to infectious diseases where activeinfection exists at any body site, such as septic shock, disseminatedintravascular coagulation, and/or adult respiratory distress syndrome;acute or chronic inflammation due to antigen, antibody and/or complementdeposition; inflammatory conditions including arthritis, cholangitis,colitis, encephalitis, endocarditis, glomerulonephritis, hepatitis,myocarditis, pancreatitis, pericarditis, reperfusion injury andvasculitis, immune-based diseases such as acute and delayedhypersensitivity, graft rejection, and graft-versus-host disease;auto-immune diseases including Type 1 diabetes mellitus and multiplesclerosis. For example, the condition, disease or disorder may be aninflammatory disorder such as rheumatoid arthritis, osteoarthritis,septic shock, COPD and periodontal disease.

In some embodiments, the condition, disease or disorder is an autoimmunediseases. Non-limiting examples include rheumatoid arthritis, systemiclupus erythematosus, multiple sclerosis, inflammatory bowel diseases(IBDs) comprising Crohn disease (CD) and ulcerative colitis (UC), whichare chronic inflammatory conditions with polygenic susceptibility. Incertain embodiments, the condition is an inflammatory bowel disease. Incertain embodiments, the condition is Crohn's disease, autoimmunecolitis, iatrogenic autoimmune colitis, ulcerative colitis, colitisinduced by one or more chemotherapeutic agents, colitis induced bytreatment with adoptive cell therapy, colitis associated by one or morealloimmune diseases (such as graft-vs-host disease, e.g., acute graftvs. host disease and chronic graft vs. host disease), radiationenteritis, collagenous colitis, lymphocytic colitis, microscopiccolitis, and radiation enteritis. In certain of these embodiments, thecondition is alloimmune disease (such as graft-vs-host disease, e.g.,acute graft vs. host disease and chronic graft vs. host disease), celiacdisease, irritable bowel syndrome, rheumatoid arthritis, lupus,scleroderma, psoriasis, cutaneous T-cell lymphoma, uveitis, andmucositis (e.g., oral mucositis, esophageal mucositis or intestinalmucositis).

In some embodiments, the condition, disease or disorder is selected frommajor adverse cardiovascular events such as carbiovascular death,non-fatal myocardial infarction and non-fatal stroke in patients with aprior hear attack and inflammatory atherosclerosis (see for example,NCT01327846).

In some embodiments, the condition, disease or disorder is selected frommetabolic disorders such as type 2 diabetes, atherosclerosis, obesityand gout, as well as diseases of the central nervous system, such asAlzheimer's disease and multiple sclerosis and Amyotrophic LateralSclerosis and Parkinson disease, lung disease, such as asthma and COPDand pulmonary idiopathic fibrosis, liver disease, such as NASH syndrome,viral hepatitis and cirrhosis, pancreatic disease, such as acute andchronic pancreatitis, kidney disease, such as acute and chronic kidneyinjury, intestinal disease such as Crohn's disease and UlcerativeColitis, skin disease such as psoriasis, musculoskeletal disease such asscleroderma, vessel disorders, such as giant cell arteritis, disordersof the bones, such as Osteoarthritis, osteoporosis and osteopetrosisdisorders eye disease, such as glaucoma and macular degeneration,diseased caused by viral infection such as HIV and AIDS, autoimmunedisease such as Rheumatoid Arthritis, Systemic Lupus Erythematosus,Autoimmune Thyroiditis, Addison's disease, pernicious anemia, cancer andaging.

In some embodiments, the condition, disease or disorder is acardiovascular indication. In some embodiments, the condition, diseaseor disorder is myocardial infraction. In some embodiments, thecondition, disease or disorder is stroke.

In some embodiments, the condition, disease or disorder is obesity.

In some embodiments, the condition, disease or disorder is Type 2Diabetes.

In some embodiments, the condition, disease or disorder is NASH.

In some embodiments, the condition, disease or disorder is Alzheimer'sdisease.

In some embodiments, the condition, disease or disorder is gout.

In some embodiments, the condition, disease or disorder is SLE.

In some embodiments, the condition, disease or disorder is rheumatoidarthritis.

In some embodiments, the condition, disease or disorder is IBD.

In some embodiments, the condition, disease or disorder is multiplesclerosis.

In some embodiments, the condition, disease or disorder is COPD.

In some embodiments, the condition, disease or disorder is asthma.

In some embodiments, the condition, disease or disorder is scleroderma.

In some embodiments, the condition, disease or disorder is pulmonaryfibrosis.

In some embodiments, the condition, disease or disorder is age relatedmacular degeneration (AMD).

In some embodiments, the condition, disease or disorder is cysticfibrosis.

In some embodiments, the condition, disease or disorder is Muckle Wellssyndrome.

In some embodiments, the condition, disease or disorder is familial coldautoinflammatory syndrome (FCAS).

In some embodiments, the condition, disease or disorder is chronicneurologic cutaneous and articular syndrome.

In some embodiments, the condition, disease or disorder is selectedfrom: myelodysplastic syndromes (MDS); non-small cell lung cancer, suchas non-small cell lung cancer in patients carrying mutation oroverexpression of NLRP3; acute lymphoblastic leukemia (ALL), such as ALLin patients resistant to glucocorticoids treatment; Langerhan's cellhistiocytosis (LCH); multiple myeloma; promyelocytic leukemia; acutemyeloid leukemia (AML) chronic myeloid leukemia (CIVIL); gastric cancer;and lung cancer metastasis.

In some embodiments, the condition, disease or disorder is selectedfrom: myelodysplastic syndromes (MDS); non-small cell lung cancer, suchas non-small cell lung cancer in patients carrying mutation oroverexpression of NLRP3; acute lymphoblastic leukemia (ALL), such as ALLin patients resistant to glucocorticoids treatment; Langerhan's cellhistiocytosis (LCH); multiple myeloma; promyelocytic leukemia; gastriccancer; and lung cancer metastasis.

In some embodiments, the indication is MDS.

In some embodiments, the indication is non-small lung cancer in patientscarrying mutation or overexpression of NLRP3.

In some embodiments, the indication is ALL in patients resistant toglucocorticoids treatment.

In some embodiments, the indication is LCH.

In some embodiments, the indication is multiple myeloma.

In some embodiments, the indication is promyelocytic leukemia.

In some embodiments, the indication is gastric cancer.

In some embodiments, the indication is lung cancer metastasis.

Combination Therapy

This disclosure contemplates both monotherapy regimens as well ascombination therapy regimens.

In some embodiments, the methods described herein can further includeadministering one or more additional therapies (e.g., one or moreadditional therapeutic agents and/or one or more therapeutic regimens)in combination with administration of the compounds described herein.

In certain embodiments, the second therapeutic agent or regimen isadministered to the subject prior to contacting with or administeringthe chemical entity (e.g., about one hour prior, or about 6 hours prior,or about 12 hours prior, or about 24 hours prior, or about 48 hoursprior, or about 1 week prior, or about 1 month prior).

In other embodiments, the second therapeutic agent or regimen isadministered to the subject at about the same time as contacting with oradministering the chemical entity. By way of example, the secondtherapeutic agent or regimen and the chemical entity are provided to thesubject simultaneously in the same dosage form. As another example, thesecond therapeutic agent or regimen and the chemical entity are providedto the subject concurrently in separate dosage forms.

In still other embodiments, the second therapeutic agent or regimen isadministered to the subject after contacting with or administering thechemical entity (e.g., about one hour after, or about 6 hours after, orabout 12 hours after, or about 24 hours after, or about 48 hours after,or about 1 week after, or about 1 month after).

Patient Selection

In some embodiments, the methods described herein further include thestep of identifying a subject (e.g., a patient) in need of treatment foran indication related to NLRP3 activity, such as an indication relatedto NLRP3 polymorphism.

In some embodiments, the methods described herein further include thestep of identifying a subject (e.g., a patient) in need of treatment foran indication related to NLRP3 activity, such as an indication relatedto NLRP3 where polymorphism is a gain of function

In some embodiments, the methods described herein further include thestep of identifying a subject (e.g., a patient) in need of treatment foran indication related to NLRP3 activity, such as an indication relatedto NLRP3 polymorphism found in CAPS syndromes.

In some embodiments, the methods described herein further include thestep of identifying a subject (e.g., a patient) in need of treatment foran indication related to NLRP3 activity, such as an indication relatedNLRP3 polymorphism where the polymorphism is VAR_014104 (R262W)

In some embodiments, the methods described herein further include thestep of identifying a subject (e.g., a patient) in need of treatment foran indication related to NLRP3 activity, such as an indication relatedNLRP3 polymorphism where the polymorphism is a natural variant reportedin http://www.uniprot.org/uniprot/Q96P20.

In some embodiments, the methods described herein further include thestep of identifying a subject (e.g., a patient) in need of treatment foran indication related to NLRP3 activity, such as an indication relatedto point mutation of NLRP3 signaling.

Anti-TNFα Agents

The term “anti-TNFα agent” refers to an agent which directly orindirectly blocks, down-regulates, impairs, inhibits, impairs, orreduces TNFα activity and/or expression. In some embodiments, ananti-TNFα agent is an antibody or an antigen-binding fragment thereof, afusion protein, a soluble TNFα receptor (a soluble tumor necrosis factorreceptor superfamily member 1A (TNFR1) or a soluble tumor necrosisfactor receptor superfamily 1B (TNFR2)), an inhibitory nucleic acid, ora small molecule TNFα antagonist. In some embodiments, the inhibitorynucleic acid is a ribozyme, small hairpin RNA, a small interfering RNA,an antisense nucleic acid, or an aptamer.

Exemplary anti-TNFα agents that directly block, down-regulate, impair,inhibit, or reduce TNFα activity and/or expression can, e.g., inhibit ordecrease the expression level of TNFα or a receptor of TNFα (TNFR1 orTNFR2) in a cell (e.g., a cell obtained from a subject, a mammaliancell), or inhibit or reduce binding of TNFα to its receptor (TNFR1and/or TNFR2) and/or. Non-limiting examples of anti-TNFα agents thatdirectly block, down-regulate, impair, inhibit, or reduce TNFα activityand/or expression include an antibody or fragment thereof, a fusionprotein, a soluble TNFα receptor (e.g., a soluble TNFR1 or solubleTNFR2), inhibitory nucleic acids (e.g., any of the examples ofinhibitory nucleic acids described herein), and a small molecule TNFαantagonist.

Exemplary anti-TNFα agents that can indirectly block, down-regulate,impair, inhibitreduce TNFα activity and/or expression can, e.g., inhibitor decrease the level of downstream signaling of a TNFα receptor (e.g.,TNFR1 or TNFR2) in a mammalian cell (e.g., decrease the level and/oractivity of one or more of the following signaling proteins: AP-1,mitogen-activated protein kinase kinase kinase 5 (ASK1), inhibitor ofnuclear factor kappa B (IKK), mitogen-activated protein kinase 8 (JNK),mitogen-activated protein kinase (MAPK), MEKK 1/4, MEKK 4/7, MEKK 3/6,nuclear factor kappa B (NF-κB), mitogen-activated protein kinase kinasekinase 14 (NIK), receptor interacting serine/threonine kinase 1 (RIP),TNFRSF1A associated via death domain (TRADD), and TNF receptorassociated factor 2 (TRAF2), in a cell), and/or decrease the level ofTNFa-induced gene expression in a mammalian cell (e.g., decrease thetranscription of genes regulated by, e.g., one or more transcriptionfactors selected from the group of activating transcription factor 2(ATF2), c-Jun, and NF-κB). A description of downstream signaling of aTNFα receptor is provided in Wajant et al., Cell Death Differentiation10:45-65, 2003 (incorporated herein by reference). For example, suchindirect anti-TNFα agents can be an inhibitory nucleic acid that targets(decreases the expression) a signaling component downstream of aTNFa-induced gene (e.g., any TNFa-induced gene known in the art), a TNFαreceptor (e.g., any one or more of the signaling components downstreamof a TNFα receptor described herein or known in the art), or atranscription factor selected from the group of NF-κB, c-Jun, and ATF2.

In other examples, such indirect anti-TNFα agents can be a smallmolecule inhibitor of a protein encoded by a TNFα-induced gene (e.g.,any protein encoded by a TNFα-induced gene known in the art), a smallmolecule inhibitor of a signaling component downstream of a TNFαreceptor (e.g., any of the signaling components downstream of a TNFαreceptor described herein or known in the art), and a small moleculeinhibitor of a transcription factor selected from the group of ATF2,c-Jun, and NF-κB.

In other embodiments, anti-TNFα agents that can indirectly block,down-regulate, impair, or reduce one or more components in a cell (e.g.,a cell obtained from a subject, a mammalian cell) that are involved inthe signaling pathway that results in TNFα mRNA transcription, TNFα mRNAstabilization, and TNFα mRNA translation (e.g., one or more componentsselected from the group of CD14, c-Jun, ERK1/2, IKK, IxB, interleukin 1receptor associated kinase 1 (IRAK), JNK, lipopolysaccharide bindingprotein (LBP), MEK1/2, MEK3/6, MEK4/7, MK2, MyD88, NF-κB, NIK, PKR, p38,AKT serine/threonine kinase 1 (rac), raf kinase (raf), ras, TRAF6, TTP).For example, such indirect anti-TNFα agents can be an inhibitory nucleicacid that targets (decreases the expression) of a component in amammalian cell that is involved in the signaling pathway that results inTNFα mRNA transcription, TNFα mRNA stabilization, and TNFα mRNAtranslation (e.g., a component selected from the group of CD14, c-Jun,ERK1/2, IKK, IκB, IRAK, JNK, LBP, MEK1/2, MEK3/6, MEK4/7, MK2, MyD88,NF-κB, NIK, IRAK, lipopolysaccharide binding protein (LBP), PKR, p38,rac, raf, ras, TRAF6, TTP). In other examples, an indirect anti-TNFαagents is a small molecule inhibitor of a component in a mammalian cellthat is involved in the signaling pathway that results in TNFα mRNAtranscription, TNFα mRNA stabilization, and TNFα mRNA translation (e.g.,a component selected from the group of CD14, c-Jun, ERK1/2, IKK, IκB,IRAK, JNK, lipopolysaccharide binding protein (LBP), MEK1/2, MEK3/6,MEK4/7, MK2, MyD88, NF-κB, NIK, IRAK, lipopolysaccharide binding protein(LBP), PKR, p38, rac, raf, ras, TRAF6, TTP).

Antibodies

In some embodiments, the anti-TNFα agent is an antibody or anantigen-binding fragment thereof (e.g., a Fab or a scFv). In someembodiments, an antibody or antigen-binding fragment of an antibodydescribed herein can bind specifically to TNFα. In some embodiments, anantibody or antigen-binding fragment described herein binds specificallyto any one of TNFα, TNFR1, or TNFR2. In some embodiments, an antibody orantigen-binding fragment of an antibody described herein can bindspecifically to a TNFα receptor (TNFR1 or TNFR2).

In some embodiments, the antibody can be a humanized antibody, achimeric antibody, a multivalent antibody, or a fragment thereof. Insome embodiments, an antibody can be a scFv-Fc, a VHH domain, a VNARdomain, a (scFv)₂, a minibody, or a BiTE.

In some embodiments, an antibody can be a crossmab, a diabody, ascDiabody, a scDiabody-CH3, a Diabody-CH3, a DutaMab, a DT-IgG, adiabody-Fc, a scDiabody-HAS, a charge pair antibody, a Fab-arm exchangeantibody, a SEEDbody, a Triomab, a LUZ-Y, a Fcab, a kλ-body, anorthogonal Fab, a DVD-IgG, an IgG(H)-scFv, a scFv-(H)IgG, anIgG(L)-scFv, a scFv-(L)-IgG, an IgG (L,H)-Fc, an IgG(H)-V, a V(H)-IgG,an IgG(L)-V, a V(L)-IgG, an KIH IgG-scFab, a 2 scFv-IgG, an IgG-2 scFv,a scFv4-Ig, a Zybody, a DVI-IgG, a nanobody, a nanobody-HSA, a DVD-Ig, adual-affinity re-targeting antibody (DART), a triomab, a kih IgG with acommon LC, an ortho-Fab IgG, a 2-in-1-IgG, IgG-ScFv, scFv2-Fc, abi-nanobody, tanden antibody, a DART-Fc, a scFv-HAS-scFv, a DAF(two-in-one or four-in-one), a DNL-Fab3, knobs-in-holes common LC,knobs-in-holes assembly, a TandAb, a Triple Body, a miniantibody, aminibody, a TriBi minibody, a scFv-CH₃ KIH, a Fab-scFv, ascFv-CH-CL-scFv, a F(ab′)₂-scFV2, a scFv-KIH, a Fab-scFv-Fc, atetravalent HCAb, a scDiabody-Fc, a tandem scFv-Fc, an intrabody, a dockand lock bispecific antibody, an ImmTAC, a HSAbody, a tandem scFv, anIgG-IgG, a Cov-X-Body, and a scFv1-PEG-scFv2.

Non-limiting examples of an antigen-binding fragment of an antibodyinclude an Fv fragment, a Fab fragment, a F(ab′)₂ fragment, and a Fab′fragment. Additional examples of an antigen-binding fragment of anantibody is an antigen-binding fragment of an antigen-binding fragmentof an IgA (e.g., an antigen-binding fragment of IgA1 or IgA2) (e.g., anantigen-binding fragment of a human or humanized IgA, e.g., a human orhumanized IgA1 or IgA2); an antigen-binding fragment of an IgD (e.g., anantigen-binding fragment of a human or humanized IgD); anantigen-binding fragment of an IgE (e.g., an antigen-binding fragment ofa human or humanized IgE); an IgG (e.g., an antigen-binding fragment ofIgG1, IgG2, IgG3, or IgG4) (e.g., an antigen-binding fragment of a humanor humanized IgG, e.g., human or humanized IgG1, IgG2, IgG3, or IgG4);or an antigen-binding fragment of an IgM (e.g., an antigen-bindingfragment of a human or humanized IgM).

Non-limiting examples of anti-TNFα agents that are antibodies thatspecifically bind to TNFα are described in Ben-Horin et al.,Autoimmunity Rev. 13(1):24-30, 2014; Bongartz et al., JAMA295(19):2275-2285, 2006; Butler et al., Eur. Cytokine Network6(4):225-230, 1994; Cohen et al., Canadian J Gastroenterol. Hepatol.15(6):376-384, 2001; Elliott et al., Lancet 1994; 344: 1125-1127, 1994;Feldmann et al., Ann. Rev. Immunol. 19(1):163-196, 2001; Rankin et al.,Br. J Rheumatol. 2:334-342, 1995; Knight et al., Molecular Immunol.30(16):1443-1453, 1993; Lorenz et al., J. Immunol. 156(4):1646-1653,1996; Hinshaw et al., Circulatory Shock 30(3):279-292, 1990; Ordas etal., Clin. Pharmacol. Therapeutics 91(4):635-646, 2012; Feldman, NatureReviews Immunol. 2(5):364-371, 2002; Taylor et al., Nature ReviewsRheumatol. 5(10):578-582, 2009; Garces et al., Annals Rheumatic Dis.72(12):1947-1955, 2013; Palladino et al., Nature Rev. Drug Discovery2(9):736-746, 2003; Sandborn et al., Inflammatory Bowel Diseases5(2):119-133, 1999; Atzeni et al., Autoimmunity Reviews 12(7):703-708,2013; Maini et al., Immunol. Rev. 144(1):195-223, 1995; Wanner et al.,Shock 11(6):391-395, 1999; and U.S. Pat. Nos. 6,090,382; 6,258,562; and6,509,015).

In certain embodiments, the anti-TNFα agent can include or is golimumab(Golimumab™), adalimumab (Humira™), infliximab (Remicade™), CDP571, CDP870, or certolizumab pegol (Cimzia™). In certain embodiments, theanti-TNFα agent can be a TNFα inhibitor biosimilar. Examples of approvedand late-phase TNFα inhibitor biosimilars include, but are not limitedto, infliximab biosimilars such as Flixabi™ (SB2) from Samsung Bioepis,Inflectra® (CT-P13) from Celltrion/Pfizer, GS071 from Aprogen, Remsima™,PF-06438179 from Pfizer/Sandoz, NI-071 from Nichi-Iko PharmaceuticalCo., and ABP 710 from Amgen; adalimumab biosimilars such as Amgevita®(ABP 501) from Amgen and Exemptia™ from Zydus Cadila, BMO-2 orMYL-1401-A from Biocon/Mylan, CHS-1420 from Coherus, FKB327 from KyowaKirin, and BI 695501 from Boehringer Ingelheim; Solymbic®, SB5 fromSamsung Bioepis, GP-2017 from Sandoz, ONS-3010 from Oncobiologics, M923from Momenta, PF-06410293 from Pfizer, and etanercept biosimilars suchas Erelzi™ from Sandoz/Novartis, Brenzys™ (SB4) from Samsung Bioepis,GP2015 from Sandoz, TuNEX® from Mycenax, LBEC0101 from LG Life, andCHS-0214 from Coherus.

In some embodiments of any of the methods described herein, theanti-TNFα agent is selected from the group consisting of: adalimumab,certolizumab, etanercept, golimumab, infliximabm, CDP571, and CDP 870.

In some embodiments, any of the antibodies or antigen-binding fragmentsdescribed herein has a dissociation constant (K_(D)) of less than1×10⁻⁵M (e.g., less than 0.5×10⁻⁵M, less than 1×10⁻⁶ M, less than0.5×10⁻⁶ M, less than 1×10⁻⁷M, less than 0.5×10⁻⁷M, less than 1×10⁻⁸M,less than 0.5×10⁻⁸M, less than 1×10⁻⁹M, less than 0.5×10⁻⁹M, less than1×10⁻¹⁰ M, less than 0.5×10⁻¹⁰ M, less than 1×10⁻¹¹ M less than0.5×10⁻¹¹ M, or less than 1×10⁻¹²M), e.g., as measured in phosphatebuffered saline using surface plasmon resonance (SPR).

In some embodiments, any of the antibodies or antigen-binding fragmentsdescribed herein has a K_(D) of about 1×10⁻¹²M to about 1×10⁻⁵M, about0.5×10⁻⁵M, about 1×10⁻⁶ M, about 0.5×10⁻⁶ M, about 1×10⁻⁷M, about0.5×10⁻⁷M, about 1×10⁻⁸M, about 0.5×10⁻⁸M, about 1×10⁻⁹M, about0.5×10⁻⁹M, about 1×10⁻¹⁰ M about 0.5×10⁻¹⁰ M, about 1×10⁻¹¹M, or about0.5×10⁻¹¹M (inclusive); about 0.5×10⁻¹¹M to about 1×10⁻⁵M, about0.5×10⁻⁵M, about 1×10⁻⁶ M, about 0.5×10⁻⁶ M, about 1×10⁻⁷M, about0.5×10⁻⁷M, about 1×10⁻⁸M, about 0.5×10⁻⁸M, about 1×10⁻⁹M, about0.5×10⁻⁹M, about 1×10⁻¹⁰ M, about 0.5×10⁻¹⁰ M, or about 1×10⁻¹¹M(inclusive); about 1×10⁻¹¹M to about 1×10⁻⁵M, about 0.5×10⁻⁵M, about1×10⁻⁶ M, about 0.5×10⁻⁶ M, about 1×10⁻⁷M, about 0.5×10⁻⁷M, about1×10⁻⁸M, about 0.5×10⁻⁸M, about 1×10⁻⁹M, about 0.5×10⁻⁹M, about 1×10⁻¹⁰M, or about 0.5×10⁻¹⁰ M (inclusive); about 0.5×10⁻¹⁰ M to about 1×10⁻⁵M,about 0.5×10⁻⁵M, about 1×10⁻⁶ M, about 0.5×10⁻⁶ M, about 1×10⁻⁷M, about0.5×10⁻⁷M, about 1×10⁻⁸M, about 0.5×10⁻⁸M, about 1×10⁻⁹M, about0.5×10⁻⁹M, or about 1×10⁻¹⁰ M (inclusive); about 1×10⁻¹⁰ M to about1×10⁻⁵M, about 0.5×10⁻⁵ M, about 1×10⁻⁶ M, about 0.5×10⁻⁶ M, about1×10⁻⁷M, about 0.5×10⁻⁷M, about 1×10⁻⁸M, about 0.5×10⁻⁸M, about 1×10⁻⁹M,or about 0.5×10⁻⁹M (inclusive); about 0.5×10⁻⁹M to about 1×10⁻⁵M, about0.5×10⁻⁵M, about 1×10⁻⁶ M, about 0.5×10⁻⁶ M, about 1×10⁻⁷M, about0.5×10⁻⁷M, about 1×10⁻⁸M, about 0.5×10⁻⁸M, or about 1×10⁻⁹M (inclusive);about 1×10⁻⁹M to about 1×10⁻⁵M, about 0.5×10⁻⁵M, about 1×10⁻⁶ M, about0.5×10⁻⁶ M, about 1×10⁻⁷M, about 0.5×10⁻⁷M, about 1×10⁻⁸M, or about0.5×10⁻⁸M (inclusive); about 0.5×10⁻⁸ M to about 1×10⁻⁵M, about0.5×10⁻⁵M, about 1×10⁻⁶ M, about 0.5×10⁻⁶ M, about 1×10⁻⁷ M, about0.5×10⁻⁷M, or about 1×10⁻⁸M (inclusive); about 1×10⁻⁸M to about 1×10⁻⁵M,about 0.5×10⁻⁵M, about 1×10⁻⁶ M, about 0.5×10⁻⁶ M, about 1×10⁻⁷M, orabout 0.5×10⁻⁷M (inclusive); about 0.5×10⁻⁷ M to about 1×10⁻⁵M, about0.5×10⁻⁵ M, about 1×10⁻⁶ M, about 0.5×10⁻⁶ M, or about 1×10⁻⁷M(inclusive); about 1×10⁻⁷ M to about 1×10⁻⁵M, about 0.5×10⁻⁵ M, about1×10⁻⁶ M, or about 0.5×10⁻⁶ M (inclusive); about 0.5×10⁻⁶ M to about1×10⁻⁵ M, about 0.5×10⁻⁵ M, or about 1×10⁻⁶ M (inclusive); about 1×10⁻⁶M to about 1×10⁻⁵M or about 0.5×10⁻⁵ M (inclusive); or about 0.5×10⁻⁵Mto about 1×10⁻⁵M (inclusive), e.g., as measured in phosphate bufferedsaline using surface plasmon resonance (SPR).

In some embodiments, any of the antibodies or antigen-binding fragmentsdescribed herein has a K_(off) of about 1×10⁻⁶ s⁻¹ to about 1×10⁻³ s⁻¹,about 0.5×10⁻³ s⁻¹, about 1×10's⁻¹, about 0.5×10⁻⁴ s⁻¹, about 1×10⁻⁵s⁻¹, or about 0.5×10⁻⁵ s⁻¹ (inclusive); about 0.5×10⁻⁵ s⁻¹ to about1×10⁻³ s⁻¹, about 0.5×10⁻³ s⁻¹, about 1×10's⁻¹, about 0.5×10's⁻¹, orabout 1×10⁻⁵ s⁻¹ (inclusive); about 1×10⁻⁵ s⁻¹ to about 1×10⁻³ s⁻¹,about 0.5×10⁻³ s⁻¹, about 1×10's⁻¹, or about 0.5×10⁻⁴ s⁻¹ (inclusive);about 0.5×10's⁻¹ to about 1×10⁻³ s⁻¹, about 0.5×10⁻³ s⁻¹, or about1×10⁻⁴ s⁻¹ (inclusive); about 1×10's⁻¹ to about 1×10⁻³ s⁻¹, or about0.5×10⁻³ s⁻¹ (inclusive); or about 0.5×10⁻⁵ s⁻¹ to about 1×10⁻³ s⁻¹(inclusive), e.g., as measured in phosphate buffered saline usingsurface plasmon resonance (SPR).

In some embodiments, any of the antibodies or antigen-binding fragmentsdescribed herein has a K_(on) of about 1×10² M⁻¹ s⁻¹ to about 1×10⁶M⁻¹s⁻¹, about 0.5×10⁶ M⁻¹ s⁻¹, about 1×10⁵M⁻¹ s⁻¹, about 0.5×10⁵ M⁻¹ s⁻¹,about 1×10⁴ M⁻¹, s⁻¹ about 0.5×10⁴ M⁻¹ s⁻¹, about 1×10³ M⁻¹ s⁻¹, orabout 0.5×10³ M⁻¹ s⁻¹ (inclusive); about 0.5×10³ M⁻¹ s⁻¹ to about1×10⁶M⁻¹ s⁻¹, about 0.5×10⁶ M⁻¹, s⁻¹ about 1×10⁵M⁻¹ s⁻¹, about 0.5×10⁵M⁻¹ s⁻¹, about 1×10⁴ M⁻¹ s⁻¹, about 0.5×10⁴ M⁻¹ s⁻¹, or about 1×10³ M⁻¹s⁻¹ (inclusive); about 1×10³ M⁻¹ s⁻¹ to about 1×10⁶M⁻¹ s⁻¹, about0.5×10⁶M⁻¹ s⁻¹ about 1×10⁵M⁻¹ s⁻¹, about 0.5×10⁵ M⁻¹ s⁻¹, about 1×10⁴M⁻¹ s⁻¹, or about 0.5×10⁴ M⁻¹ s⁻¹ (inclusive); about 0.5×10⁴ M⁻¹ s⁻¹ toabout 1×10⁶M⁻¹ s⁻¹, about 0.5×10⁶ M⁻¹ s⁻¹, about 1×10⁵M⁻¹ s⁻¹, about0.5×10⁵ M⁻¹ s⁻¹, or about 1×10⁴M⁻¹ s⁻¹ (inclusive); about 1×10⁴ M⁻¹ s⁻¹to about 1×10⁶ M⁻¹ s⁻¹, about 0.5×10⁶ M⁻¹ s⁻¹, about 1×10⁵M⁻¹ s⁻¹, orabout 0.5×10⁵ M⁻¹ s⁻¹ (inclusive); about 0.5×10⁵ M⁻¹ s⁻¹ to about 1×10⁶M⁻¹ s⁻¹, about 0.5×10⁶ M⁻¹ s⁻¹, or about 1×10⁵ M⁻¹ s⁻¹ (inclusive);about 1×10⁵M⁻¹ s⁻¹ to about 1×10⁶M⁻¹ s⁻¹, or about 0.5×10⁶ M⁻¹ s⁻¹(inclusive); or about 0.5×10⁶ M⁻¹ s⁻¹ to about 1×10⁶M⁻¹ s⁻¹ (inclusive),e.g., as measured in phosphate buffered saline using surface plasmonresonance (SPR).

Fusion Proteins

In some embodiments, the anti-TNFα agent is a fusion protein (e.g., anextracellular domain of a TNFR fused to a partner peptide, e.g., an Fcregion of an immunoglobulin, e.g., human IgG) (see, e.g., Deeg et al.,Leukemia 16(2):162, 2002; Peppel et al., J. Exp. Med. 174(6):1483-1489,1991) or a soluble TNFR (e.g., TNFR1 or TNFR2) that binds specificallyto TNFα. In some embodiments, the anti-TNFα agent includes or is asoluble TNFα receptor (e.g., Bjornberg et al., Lymphokine Cytokine Res.13(3):203-211, 1994; Kozak et al., Am. J. Physiol. Reg. IntegrativeComparative Physiol. 269(1):R23-R29, 1995; Tsao et al., Eur Respir14(3):490-495, 1999; Watt et al., J Leukoc Biol. 66(6):1005-1013, 1999;Mohler et al., J. Immunol. 151(3):1548-1561, 1993; Nophar et al., EMBO J9(10):3269, 1990; Piguet et al., Eur. Respiratory 7(3):515-518, 1994;and Gray et al., Proc. Natl. Acad. Sci. U.S.A. 87(19):7380-7384, 1990).In some embodiments, the anti-TNFα agent includes or is etanercept(Enbrel™) (see, e.g., WO 91/03553 and WO 09/406,476, incorporated byreference herein). In some embodiments, the anti-TNFα agent inhibitorincludes or is r-TBP-I (e.g., Gradstein et al., J. Acquir. Immune Defic.Syndr. 26(2): 111-117, 2001).

Inhibitory Nucleic Acids

Inhibitory nucleic acids that can decrease the expression of AP-1, ASK1,CD14, c-jun, ERK1/2, IκB, IKK, IRAK, JNK, LBP, MAPK, MEK1/2, MEKK1/4,MEKK4/7, MEKK 3/6, MK2, MyD88, NF-κB, NIK, p38, PKR, rac, ras, raf, RIP,TNFα, TNFR1, TNFR2, TRADD, TRAF2, TRAF6, or TTP mRNA expression in amammalian cell include antisense nucleic acid molecules, i.e., nucleicacid molecules whose nucleotide sequence is complementary to all or partof a AP-1, ASK1, CD14, c-jun, ERK1/2, IκB, IKK, IRAK, JNK, LBP, MAPK,MEK1/2, MEKK1/4, MEKK4/7, MEKK 3/6, MK2, MyD88, NF-κB, NIK, p38, PKR,rac, ras, raf, RIP, TNFα, TNFR1, TNFR2, TRADD, TRAF2, TRAF6, or TTP mRNA(e.g., complementary to all or a part of any one of SEQ ID NOs: 1-37).

Human TNFα CDS (SEQ ID NO: 1)ATGAGCACTGAAAGCATGATCCGGGACGTGGAGCTGGCCGAGGAGGCGCTCCCCAAGAAGACAGGGGGGCCCCAGGGCTCCAGGCGGTGCTTGTTCCTCAGCCTCTTCTCCTTCCTGATCGTGGCAGGCGCCACCACGCTCTTCTGCCTGCTGCACTTTGGAGTGATCGGCCCCCAGAGGGAAGAGTTCCCCAGGGACCTCTCTCTAATCAGCCCTCTGGCCCAGGCAGTCAGATCATCTTCTCGAACCCCGAGTGACAAGCCTGTAGCCCATGTTGTAGCAAACCCTCAAGCTGAGGGGCAGCTCCAGTGGCTGAACCGCCGGGCCAATGCCCTCCTGGCCAATGGCGTGGAGCTGAGAGATAACCAGCTGGTGGTGCCATCAGAGGGCCTGTACCTCATCTACTCCCAGGTCCTCTTCAAGGGCCAAGGCTGCCCCTCCACCCATGTGCTCCTCACCCACACCATCAGCCGCATCGCCGTCTCCTACCAGACCAAGGTCAACCTCCTCTCTGCCATCAAGAGCCCCTGCCAGAGGGAGACCCCAGAGGGGGCTGAGGCCAAGCCCTGGTATGAGCCCATCTATCTGGGAGGGGTCTTCCAGCTGGAGAAGGGTGACCGACTCAGCGCTGAGATCAATCGGCCCGACTATCTCGACTTTGCCGAGTCTGGGCAGGTCTACTTTGG GATCATTGCCCTGTGAHuman TNFR1 CDS (SEQ ID NO: 2)ATGGGCCTCTCCACCGTGCCTGACCTGCTGCTGCCACTGGTGCTCCTGGAGCTGTTGGTGGGAATATACCCCTCAGGGGTTATTGGACTGGTCCCTCACCTAGGGGACAGGGAGAAGAGAGATAGTGTGTGTCCCCAAGGAAAATATATCCACCCTCAAAATAATTCGATTTGCTGTACCAAGTGCCACAAAGGAACCTACTTGTACAATGACTGTCCAGGCCCGGGGCAGGATACGGACTGCAGGGAGTGTGAGAGCGGCTCCTTCACCGCTTCAGAAAACCACCTCAGACACTGCCTCAGCTGCTCCAAATGCCGAAAGGAAATGGGTCAGGTGGAGATCTCTTCTTGCACAGTGGACCGGGACACCGTGTGTGGCTGCAGGAAGAACCAGTACCGGCATTATTGGAGTGAAAACCTTTTCCAGTGCTTCAATTGCAGCCTCTGCCTCAATGGGACCGTGCACCTCTCCTGCCAGGAGAAACAGAACACCGTGTGCACCTGCCATGCAGGTTTCTTTCTAAGAGAAAACGAGTGTGTCTCCTGTAGTAACTGTAAGAAAAGCCTGGAGTGCACGAAGTTGTGCCTACCCCAGATTGAGAATGTTAAGGGCACTGAGGACTCAGGCACCACAGTGCTGTTGCCCCTGGTCATTTTCTTTGGTCTTTGCCTTTTATCCCTCCTCTTCATTGGTTTAATGTATCGCTACCAACGGTGGAAGTCCAAGCTCTACTCCATTGTTTGTGGGAAATCGACACCTGAAAAAGAGGGGGAGCTTGAAGGAACTACTACTAAGCCCCTGGCCCCAAACCCAAGCTTCAGTCCCACTCCAGGCTTCACCCCCACCCTGGGCTTCAGTCCCGTGCCCAGTTCCACCTTCACCTCCAGCTCCACCTATACCCCCGGTGACTGTCCCAACTTTGCGGCTCCCCGCAGAGAGGTGGCACCACCCTATCAGGGGGCTGACCCCATCCTTGCGACAGCCCTCGCCTCCGACCCCATCCCCAACCCCCTTCAGAAGTGGGAGGACAGCGCCCACAAGCCACAGAGCCTAGACACTGATGACCCCGCGACGCTGTACGCCGTGGTGGAGAACGTGCCCCCGTTGCGCTGGAAGGAATTCGTGCGGCGCCTAGGGCTGAGCGACCACGAGATCGATCGGCTGGAGCTGCAGAACGGGCGCTGCCTGCGCGAGGCGCAATACAGCATGCTGGCGACCTGGAGGCGGCGCACGCCGCGGCGCGAGGCCACGCTGGAGCTGCTGGGACGCGTGCTCCGCGACATGGACCTGCTGGGCTGCCTGGAGGACATCGAGGAGGCGCTTTGCGGCCCCGCCGCCCTCCCGCCCGCGCCCAGTCTTCTCAGATGAHuman TNFR2 CDS (SEQ ID NO: 3)ATTCTTCCCCTGGTGGCCATGGGACCCAGGTCAATGTCACCTGCATCGTGAACGTCTGTAGCAGCTCTGACCACAGCTCACAGTGCTCCTCCCAAGCCAGCTCCACAATGGGAGACACAGATTCCAGCCCCTCGGAGTCCCCGAAGGACGAGCAGGTCCCCTTCTCCAAGGAGGAATGTGCCTTTCGGTCACAGCTGGAGACGCCAGAGACCCTGCTGGGGAGCACCGAAGAGAAGCCCCTGCCCCTTGGAGTGCCTGATGCTGGGATGAAGCCCAGTTAA Human TRADD CDS (SEQ ID NO: 4)ATGGCAGCTGGGCAAAATGGGCACGAAGAGTGGGTGGGCAGCGCATACCTGTTTGTGGAGTCCTCGCTGGACAAGGTGGTCCTGTCGGATGCCTACGCGCACCCCCAGCAGAAGGTGGCAGTGTACAGGGCTCTGCAGGCTGCCTTGGCAGAGAGCGGCGGGAGCCCGGACGTGCTGCAGATGCTGAAGATCCACCGCAGCGACCCGCAGCTGATCGTGCAGCTGCGATTCTGCGGGCGGCAGCCCTGTGGCCGCTTCCTCCGCGCCTACCGCGAGGGGGCGCTGCGCGCCGCGCTGCAGAGGAGCCTGGCGGCCGCGCTCGCCCAGCACTCGGTGCCGCTGCAACTGGAGCTGCGCGCCGGCGCCGAGCGGCTGGACGCTTTGCTGGCGGACGAGGAGCGCTGTTTGAGTTGCATCCTAGCCCAGCAGCCCGACCGGCTCCGGGATGAAGAACTGGCTGAGCTGGAGGATGCGCTGCGAAATCTGAAGTGCGGCTCGGGGGCCCGGGGTGGCGACGGGGAGGTCGCTTCGGCCCCCTTGCAGCCCCCGGTGCCCTCTCTGTCGGAGGTGAAGCCGCCGCCGCCGCCGCCACCTGCCCAGACTTTTCTGTTCCAGGGTCAGCCTGTAGTGAATCGGCCGCTGAGCCTGAAGGACCAACAGACGTTCGCGCGCTCTGTGGGTCTCAAATGGCGCAAGGTGGGGCGCTCACTGCAGCGAGGCTGCCGGGCGCTGCGGGACCCGGCGCTGGACTCGCTGGCCTACGAGTACGAGCGCGAGGGACTGTACGAGCAGGCCTTCCAGCTGCTGCGGCGCTTCGTGCAGGCCGAGGGCCGCCGCGCCACGCTGCAGCGCCTGGTGGAGGCACTCGAGGAGAACGAGCTCACCAGCCTGGCAGAGGACTTGCTGGGCCTGACCGATCCCAATGGCGGCC TGGCCTAGHuman TRAF2 CDS (SEQ ID NO: 5)ATGGCTGCAGCTAGCGTGACCCCCCCTGGCTCCCTGGAGTTGCTACAGCCCGGCTTCTCCAAGACCCTCCTGGGGACCAAGCTGGAAGCCAAGTACCTGTGCTCCGCCTGCAGAAACGTCCTCCGCAGGCCCTTCCAGGCGCAGTGTGGCCACCGGTACTGCTCCTTCTGCCTGGCCAGCATCCTCAGCTCTGGGCCTCAGAACTGTGCTGCCTGTGTTCACGAGGGCATATATGAAGAAGGCATTTCTATTTTAGAAAGCAGTTCGGCCTTCCCAGATAATGCTGCCCGCAGGGAGGTGGAGAGCCTGCCGGCCGTCTGTCCCAGTGATGGATGCACCTGGAAGGGGACCCTGAAAGAATACGAGAGCTGCCACGAAGGCCGCTGCCCGCTCATGCTGACCGAATGTCCCGCGTGCAAAGGCCTGGTCCGCCTTGGTGAAAAGGAGCGCCACCTGGAGCACGAGTGCCCGGAGAGAAGCCTGAGCTGCCGGCATTGCCGGGCACCCTGCTGCGGAGCAGACGTGAAGGCGCACCACGAGGTCTGCCCCAAGTTCCCCTTAACTTGTGACGGCTGCGGCAAGAAGAAGATCCCCCGGGAGAAGTTTCAGGACCACGTCAAGACTTGTGGCAAGTGTCGAGTCCCTTGCAGATTCCACGCCATCGGCTGCCTCGAGACGGTAGAGGGTGAGAAACAGCAGGAGCACGAGGTGCAGTGGCTGCGGGAGCACCTGGCCATGCTACTGAGCTCGGTGCTGGAGGCAAAGCCCCTCTTGGGAGACCAGAGCCACGCGGGGTCAGAGCTCCTGCAGAGGTGCGAGAGCCTGGAGAAGAAGACGGCCACTTTTGAGAACATTGTCTGCGTCCTGAACCGGGAGGTGGAGAGGGTGGCCATGACTGCCGAGGCCTGCAGCCGGCAGCACCGGCTGGACCAAGACAAGATTGAAGCCCTGAGTAGCAAGGTGCAGCAGCTGGAGAGGAGCATTGGCCTCAAGGACCTGGCGATGGCTGACTTGGAGCAGAAGGTCTTGGAGATGGAGGCATCCACCTACGATGGGGTCTTCATCTGGAAGATCTCAGACTTCGCCAGGAAGCGCCAGGAAGCTGTGGCTGGCCGCATACCCGCCATCTTCTCCCCAGCCTTCTACACCAGCAGGTACGGCTACAAGATGTGTCTGCGTATCTACCTGAACGGCGACGGCACCGGGCGAGGAACACACCTGTCCCTCTTCTTTGTGGTGATGAAGGGCCCGAATGACGCCCTGCTGCGGTGGCCCTTCAACCAGAAGGTGACCTTAATGCTGCTCGACCAGAATAACCGGGAGCACGTGATTGACGCCTTCAGGCCCGACGTGACTTCATCCTCTTTTCAGAGGCCAGTCAACGACATGAACATCGCAAGCGGCTGCCCCCTCTTCTGCCCCGTCTCCAAGATGGAGGCAAAGAATTCCTACGTGCGGGACGATGCCATCTTCATCAAGGCCATTGTGGACCTGACAGGGCTCTAA Human AP-1 CDS (SEQ ID NO: 6)ATGGAAACACCCTTCTACGGCGATGAGGCGCTGAGCGGCCTGGGCGGCGGCGCCAGTGGCAGCGGCGGCAGCTTCGCGTCCCCGGGCCGCTTGTTCCCCGGGGCGCCCCCGACGGCCGCGGCCGGCAGCATGATGAAGAAGGACGCGCTGACGCTGAGCCTGAGTGAGCAGGTGGCGGCAGCGCTCAAGCCTGCGGCCGCGCCGCCTCCTACCCCCCTGCGCGCCGACGGCGCCCCCAGCGCGGCACCCCCCGACGGCCTGCTCGCCTCTCCCGACCTGGGGCTGCTGAAGCTGGCCTCCCCCGAGCTCGAGCGCCTCATCATCCAGTCCAACGGGCTGGTCACCACCACGCCGACGAGCTCACAGTTCCTCTACCCCAAGGTGGCGGCCAGCGAGGAGCAGGAGTTCGCCGAGGGCTTCGTCAAGGCCCTGGAGGATTTACACAAGCAGAACCAGCTCGGCGCGGGCGCGGCCGCTGCCGCCGCCGCCGCCGCCGCCGGGGGGCCCTCGGGCACGGCCACGGGCTCCGCGCCCCCCGGCGAGCTGGCCCCGGCGGCGGCCGCGCCCGAAGCGCCTGTCTACGCGAACCTGAGCAGCTACGCGGGCGGCGCCGGGGGCGCGGGGGGCGCCGCGACGGTCGCCTTCGCTGCCGAACCTGTGCCCTTCCCGCCGCCGCCACCCCCAGGCGCGTTGGGGCCGCCGCGCCTGGCTGCGCTCAAGGACGAGCCACAGACGGTGCCCGACGTGCCGAGCTTCGGCGAGAGCCCGCCGTTGTCGCCCATCGACATGGACACGCAGGAGCGCATCAAGGCGGAGCGCAAGCGGCTGCGCAACCGCATCGCCGCCTCCAAGTGCCGCAAGCGCAAGCTGGAGCGCATCTCGCGCCTGGAAGAGAAAGTGAAGACCCTCAAGAGTCAGAACACGGAGCTGGCGTCCACGGCGAGCCTGCTGCGCGAGCAGGTGGCGCAGCTCAAGCAGAAAGTCCTCAGCCACGTCAACAGCGGCTGCCAGCTGCTGCCCCAGCACCAG GTGCCCGCGTACTGAHuman ASK1 CDS (SEQ ID NO: 7)ATGAGCACGGAGGCGGACGAGGGCATCACTTTCTCTGTGCCACCCTTCGCCCCCTCGGGCTTCTGCACCATCCCCGAGGGCGGCATCTGCAGGAGGGGAGGAGCGGCGGCGGTGGGCGAGGGCGAGGAGCACCAGCTGCCACCGCCGCCGCCGGGCAGTTTCTGGAACGTGGAGAGCGCCGCTGCCCCTGGCATCGGTTGTCCGGCGGCCACCTCCTCGAGCAGTGCCACCCGAGGCCGGGGCAGCTCTGTTGGCGGGGGCAGCCGACGGACCACGGTGGCATATGTGATCAACGAAGCGAGCCAAGGGCAACTGGTGGTGGCCGAGAGCGAGGCCCTGCAGAGCTTGCGGGAGGCGTGCGAGACAGTGGGCGCCACCCTGGAACCCTGCATTTTGGGAAACTCGACTTTGGAGAAACCACCGTGCTGGACCGCTTTTACAATGCAGATATTGCGGTGGTGGAGATGAGCGATGCCTTCCGGCAGCCGTCCTTGTTTTACCACCTTGGGGTGAGAGAAAGTTTCAGCATGGCCAACAACATCATCCTCTACTGCGATACTAACTCGGACTCTCTGCAGTCACTGAAGGAAATCATTTGCCAGAAGAATACTATGTGCACTGGGAACTACACCTTTGTTCCTTACATGATAACTCCACATAACAAAGTCTACTGCTGTGACAGCAGCTTCATGAAGGGGTTGACAGAGCTCATGCAACCGAACTTCGAGCTGCTTCTTGGACCCATCTGCTTACCTCTTGTGGATCGTTTTATTCAACTTTTGAAGGTGGCACAAGCAAGTTCTAGCCAGTACTTCCGGGAATCTATACTCAATGACATCAGGAAAGCTCGTAATTTATACACTGGTAAAGAATTGGCAGCTGAGTTGGCAAGAATTCGGCAGCGAGTAGATAATATCGAAGTCTTGACAGCAGATATTGTCATAAATCTGTTACTTTCCTACAGAGATATCCAGGACTATGATTCTATTGTGAAGCTGGTAGAGACTTTAGAAAAACTGCCAACCTTTGATTTGGCCTCCCATCACCATGTGAAGTTTCATTATGCATTTGCACTGAATAGGAGAAATCTCCCTGGTGACAGAGCAAAAGCTCTTGATATTATGATTCCCATGGTGCAAAGCGAAGGACAAGTTGCTTCAGATATGTATTGCCTAGTTGGTCGAATCTACAAAGATATGTTTTTGGACTCTAATTTCACGGACACTGAAAGCAGAGACCATGGAGCTTCTTGGTTCAAAAAGGCATTTGAATCTGAGCCAACACTACAGTCAGGAATTAATTATGCGGTCCTCCTCCTGGCAGCTGGACACCAGTTTGAATCTTCCTTTGAGCTCCGGAAAGTTGGGGTGAAGCTAAGTAGTCTTCTTGGTAAAAAGGGAAACTTGGAAAAACTCCAGAGCTACTGGGAAGTTGGATTTTTTCTGGGGGCCAGCGTCCTAGCCAATGACCACATGAGAGTCATTCAAGCATCTGAAAAGCTTTTTAAACTGAAGACACCAGCATGGTACCTCAAGTCTATTGTAGAGACAATTTTGATATATAAGCATTTTGTGAAACTGACCACAGAACAGCCTGTGGCCAAGCAAGAACTTGTGGACTTTTGGATGGATTTCCTGGTCGAGGCCACAAAGACAGATGTTACTGTGGTTAGGTTTCCAGTATTAATATTAGAACCAACCAAAATCTATCAACCTTCTTATTTGTCTATCAACAATGAAGTTGAGGAAAAGACAATCTCTATTTGGCACGTGCTTCCTGATGACAAGAAAGGTATACATGAGTGGAATTTTAGTGCCTCTTCTGTCAGGGGAGTGAGTATTTCTAAATTTGAAGAAAGATGCTGCTTTCTTTATGTGCTTCACAATTCTGATGATTTCCAAATCTATTTCTGTACAGAACTTCATTGTAAAAAGTTTTTTGAGATGGTGAACACCATTACCGAAGAGAAGGGGAGAAGCACAGAGGAAGGAGACTGTGAAAGTGACTTGCTGGAGTATGACTATGAATATGATGAAAATGGTGACAGAGTCGTTTTAGGAAAAGGCACTTATGGGATAGTCTACGCAGGTCGGGACTTGAGCAACCAAGTCAGAATTGCTATTAAGGAAATCCCAGAGAGAGACAGCAGATACTCTCAGCCCCTGCATGAAGAAATAGCATTGCATAAACACCTGAAGCACAAAAATATTGTCCAGTATCTGGGCTCTTTCAGTGAGAATGGTTTCATTAAAATCTTCATGGAGCAGGTCCCTGGAGGAAGTCTTTCTGCTCTCCTTCGTTCCAAATGGGGTCCATTAAAAGACAATGAGCAAACAATTGGCTTTTATACAAAGCAAATACTGGAAGGATTAAAATATCTCCATGACAATCAGATAGTTCACCGGGACATAAAGGGTGACAATGTGTTGATTAATACCTACAGTGGTGTTCTCAAGATCTCTGACTTCGGAACATCAAAGAGGCTTGCTGGCATAAACCCCTGTACTGAAACTTTTACTGGTACCCTCCAGTATATGGCACCAGAAATAATAGATAAAGGACCAAGAGGCTACGGAAAAGCAGCAGACATCTGGTCTCTGGGCTGTACAATCATTGAAATGGCCACAGGAAAACCCCCATTTTATGAACTGGGAGAACCACAAGCAGCTATGTTCAAGGTGGGAATGTTTAAAGTCCACCCTGAGATCCCAGAGTCCATGTCTGCAGAGGCCAAGGCATTCATACTGAAATGTTTTGAACCAGATCCTGACAAGAGAGCCTGTGCTAACGACTTGCTTGTTGATGAGTTTTTAAAAGTTTCAAGCAAAAAGAAAAAGACACAACCTAAGCTTTCAGCTCTTTCAGCTGGATCAAATGAATATCTCAGGAGTATATCCTTGCCGGTACCTGTGCTGGTGGAGGACACCAGCAGCAGCAGTGAGTACGGCTCAGTTTCACCCGACACGGAGTTGAAAGTGGACCCCTTCTCTTTCAAAACAAGAGCCAAGTCCTGCGGAGAAAGAGATGTCAAGGGAATTCGGACACTCTTTTTGGGCATTCCAGATGAGAATTTTGAAGATCACAGTGCTCCTCCTTCCCCTGAAGAAAAAGATTCTGGATTCTTCATGCTGAGGAAGGACAGTGAGAGGCGAGCTACCCTTCACAGGATCCTGACGGAAGACCAAGACAAAATTGTGAGAAACCTAATGGAATCTTTAGCTCAGGGGGCTGAAGAACCGAAACTAAAATGGGAACACATCACAACCCTCATTGCAAGCCTCAGAGAATTTGTGAGATCCACTGACCGAAAAATCATAGCCACCACACTGTCAAAGCTGAAACTGGAGCTGGACTTCGACAGCCATGGCATTAGCCAAGTCCAGGTGGTACTCTTTGGTTTTCAAGATGCTGTCAATAAAGTTCTTCGGAATCATAACATCAAGCCGCACTGGATGTTTGCCTTAGACAGTATCATTCGGAAGGCGGTACAGACAGCCATTACCATCCTGGTTCCAGAACTAAGGCCACATTTCAGCCTTGCATCTGAGAGTGATACTGCTGATCAAGAAGACTTGGATGTAGAAGATGACCATGAGGAACAGCCTTCAAATCAAACTGTCCGAAGACCTCAGGCTGTCATTGAAGATGCTGTGGCTACCTCAGGCGTGAGCACGCTCAGTTCTACTGTGTCTCATGATTCCCAGAGTGCTCACCGGTCACTGAATGTACAGCTTGGAAGGATGAAAATAGAAACCAATAGATTACTGGAAGAATTGGTTCGGAAAGAGAAAGAATTACAAGCACTCCTTCATCGAGCTATTGAAGAAAAAGACCAAGAAATTAAACACCTGAAGCTTAAGTCCCAACCCATAGAAATTCCTGAATTGCCTGTATTTCATCTAAATTCTTCTGGCACAAATACTGAAGATTCTGAACTTACCGACTGGCTGAGAGTGAATGGAGCTGATGAAGACACTATAAGCCGGTTTTTGGCTGAAGATTATACACTATTGGATGTTCTCTACTATGTTACACGTGATGACTTAAAATGCTTGAGACTAAGGGGAGGGATGCTGTGCACACTGTGGAAGG CTATCATTGACTTTCGAAACAAA CAGACTTGAHuman CD14 CDS (SEQ ID NO: 8)ATGGAGCGCGCGTCCTGCTTGTTGCTGCTGCTGCTGCCGCTGGTGCACGTCTCTGCGACCACGCCAGAACCTTGTGAGCTGGACGATGAAGATTTCCGCTGCGTCTGCAACTTCTCCGAACCTCAGCCCGACTGGTCCGAAGCCTTCCAGTGTGTGTCTGCAGTAGAGGTGGAGATCCATGCCGGCGGTCTCAACCTAGAGCCGTTTCTAAAGCGCGTCGATGCGGACGCCGACCCGCGGCAGTATGCTGACACGGTCAAGGCTCTCCGCGTGCGGCGGCTCACAGTGGGAGCCGCACAGGTTCCTGCTCAGCTACTGGTAGGCGCCCTGCGTGTGCTAGCGTACTCCCGCCTCAAGGAACTGACGCTCGAGGACCTAAAGATAACCGGCACCATGCCTCCGCTGCCTCTGGAAGCCACAGGACTTGCACTTTCCAGCTTGCGCCTACGCAACGTGTCGTGGGCGACAGGGCGTTCTTGGCTCGCCGAGCTGCAGCAGTGGCTCAAGCCAGGCCTCAAGGTACTGAGCATTGCCCAAGCACACTCGCCTGCCTTTTCCTGCGAACAGGTTCGCGCCTTCCCGGCCCTTACCAGCCTAGACCTGTCTGACAATCCTGGACTGGGCGAACGCGGACTGATGGCGGCTCTCTGTCCCCACAAGTTCCCGGCCATCCAGAATCTAGCGCTGCGCAACACAGGAATGGAGACGCCCACAGGCGTGTGCGCCGCACTGGCGGCGGCAGGTGTGCAGCCCCACAGCCTAGACCTCAGCCACAACTCGCTGCGCGCCACCGTAAACCCTAGCGCTCCGAGATGCATGTGGTCCAGCGCCCTGAACTCCCTCAATCTGTCGTTCGCTGGGCTGGAACAGGTGCCTAAAGGACTGCCAGCCAAGCTCAGAGTGCTCGATCTCAGCTGCAACAGACTGAACAGGGCGCCGCAGCCTGACGAGCTGCCCGAGGTGGATAACCTGACACTGGACGGGAATCCCTTCCTGGTCCCTGGAACTGCCCTCCCCCACGAGGGCTCAATGAACTCCGGCGTGGTCCCAGCCTGTGCACGTTCGACCCTGTCGGTGGGGGTGTCGGGAACCCTGGTGCTGCTCCAAGGGGCCCGGGGCTTTGCCTA AHuman ERK1 CDS (SEQ ID NO: 9)ATGGCGGCGGCGGCGGCTCAGGGGGGCGGGGGCGGGGAGCCCCGTAGAACCGAGGGGGTCGGCCCGGGGGTCCCGGGGGAGGTGGAGATGGTGAAGGGGCAGCCGTTCGACGTGGGCCCGCGCTACACGCAGTTGCAGTACATCGGCGAGGGCGCGTACGGCATGGTCAGCTCGGCCTATGACCACGTGCGCAAGACTCGCGTGGCCATCAAGAAGATCAGCCCCTTCGAACATCAGACCTACTGCCAGCGCACGCTCCGGGAGATCCAGATCCTGCTGCGCTTCCGCCATGAGAATGTCATCGGCATCCGAGACATTCTGCGGGCGTCCACCCTGGAAGCCATGAGAGATGTCTACATTGTGCAGGACCTGATGGAGACTGACCTGTACAAGTTGCTGAAAAGCCAGCAGCTGAGCAATGACCATATCTGCTACTTCCTCTACCAGATCCTGCGGGGCCTCAAGTACATCCACTCCGCCAACGTGCTCCACCGAGATCTAAAGCCCTCCAACCTGCTCATCAACACCACCTGCGACCTTAAGATTTGTGATTTCGGCCTGGCCCGGATTGCCGATCCTGAGCATGACCACACCGGCTTCCTGACGGAGTATGTGGCTACGCGCTGGTACCGGGCCCCAGAGATCATGCTGAACTCCAAGGGCTATACCAAGTCCATCGACATCTGGTCTGTGGGCTGCATTCTGGCTGAGATGCTCTCTAACCGGCCCATCTTCCCTGGCAAGCACTACCTGGATCAGCTCAACCACATTCTGGGCATCCTGGGCTCCCCATCCCAGGAGGACCTGAATTGTATCATCAACATGAAGGCCCGAAACTACCTACAGTCTCTGCCCTCCAAGACCAAGGTGGCTTGGGCCAAGCTTTTCCCCAAGTCAGACTCCAAAGCCCTTGACCTGCTGGACCGGATGTTAACCTTTAACCCCAATAAACGGATCACAGTGGAGGAAGCGCTGGCTCACCCCTACCTGGAGCAGTACTATGACCCGACGGATGAGCCAGTGGCCGAGGAGCCCTTCACCTTCGCCATGGAGCTGGATGACCTACCTAAGGAGCGGCTGAAGGAGCTCATCTTCCAGGAGACAGCACGCTTCCAGCCCGGAGTGCT GGAGGCCCCCTAGHuman ERK2 CDS (SEQ ID NO: 10)ATGGCGGCGGCGGCGGCGGCGGGCGCGGGCCCGGAGATGGTCCGCGGGCAGGTGTTCGACGTGGGGCCGCGCTACACCAACCTCTCGTACATCGGCGAGGGCGCCTACGGCATGGTGTGCTCTGCTTATGATAATGTCAACAAAGTTCGAGTAGCTATCAAGAAAATCAGCCCCTTTGAGCACCAGACCTACTGCCAGAGAACCCTGAGGGAGATAAAAATCTTACTGCGCTTCAGACATGAGAACATCATTGGAATCAATGACATTATTCGAGCACCAACCATCGAGCAAATGAAAGATGTATATATAGTACAGGACCTCATGGAAACAGATCTTTACAAGCTCTTGAAGACACAACACCTCAGCAATGACCATATCTGCTATTTTCTCTACCAGATCCTCAGAGGGTTAAAATATATCCATTCAGCTAACGTTCTGCACCGTGACCTCAAGCCTTCCAACCTGCTGCTCAACACCACCTGTGATCTCAAGATCTGTGACTTTGGCCTGGCCCGTGTTGCAGATCCAGACCATGATCACACAGGGTTCCTGACAGAATATGTGGCCACACGTTGGTACAGGGCTCCAGAAATTATGTTGAATTCCAAGGGCTACACCAAGTCCATTGATATTTGGTCTGTAGGCTGCATTCTGGCAGAAATGCTTTCTAACAGGCCCATCTTTCCAGGGAAGCATTATCTTGACCAGCTGAACCACATTTTGGGTATTCTTGGATCCCCATCACAAGAAGACCTGAATTGTATAATAAATTTAAAAGCTAGGAACTATTTGCTTTCTCTTCCACACAAAAATAAGGTGCCATGGAACAGGCTGTTCCCAAATGCTGACTCCAAAGCTCTGGACTTATTGGACAAAATGTTGACATTCAACCCACACAAGAGGATTGAAGTAGAACAGGCTCTGGCCCACCCATATCTGGAGCAGTATTACGACCCGAGTGACGAGCCCATCGCCGAAGCACCATTCAAGTTCGACATGGAATTGGATGACTTGCCTAAGGAAAAGCTCAAAGAACTAATTTTTGAAGAGACTGCTAGATTCCAGCCAGGATACAGAT CTTAAHuman IKK CDS (SEQ ID NO: 11)ATGTTTTCAGGGGGGTGTCATAGCCCCGGGTTTGGCCGCCCCAGCCCCGCCTTCCCCGCCCCGGGGAGCCCGCCCCCTGCCCCGCGTCCCTGCCGACAGGAAACAGGTGAGCAGATTGCCATCAAGCAGTGCCGGCAGGAGCTCAGCCCCCGGAACCGAGAGCGGTGGTGCCTGGAGATCCAGATCATGAGAAGGCTGACCCACCCCAATGTGGTGGCTGCCCGAGATGTCCCTGAGGGGATGCAGAACTTGGCGCCCAATGACCTGCCCCTGCTGGCCATGGAGTACTGCCAAGGAGGAGATCTCCGGAAGTACCTGAACCAGTTTGAGAACTGCTGTGGTCTGCGGGAAGGTGCCATCCTCACCTTGCTGAGTGACATTGCCTCTGCGCTTAGATACCTTCATGAAAACAGAATCATCCATCGGGATCTAAAGCCAGAAAACATCGTCCTGCAGCAAGGAGAACAGAGGTTAATACACAAAATTATTGACCTAGGATATGCCAAGGAGCTGGATCAGGGCAGTCTTTGCACATCATTCGTGGGGACCCTGCAGTACCTGGCCCCAGAGCTACTGGAGCAGCAGAAGTACACAGTGACCGTCGACTACTGGAGCTTCGGCACCCTGGCCTTTGAGTGCATCACGGGCTTCCGGCCCTTCCTCCCCAACTGGCAGCCCGTGCAGTGGCATTCAAAAGTGCGGCAGAAGAGTGAGGTGGACATTGTTGTTAGCGAAGACTTGAATGGAACGGTGAAGTTTTCAAGCTCTTTACCCTACCCCAATAATCTTAACAGTGTCCTGGCTGAGCGACTGGAGAAGTGGCTGCAACTGATGCTGATGTGGCACCCCCGACAGAGGGGCACGGATCCCACGTATGGGCCCAATGGCTGCTTCAAGGCCCTGGATGACATCTTAAACTTAAAGCTGGTTCATATCTTGAACATGGTCACGGGCACCATCCACACCTACCCTGTGACAGAGGATGAGAGTCTGCAGAGCTTGAAGGCCAGAATCCAACAGGACACGGGCATCCCAGAGGAGGACCAGGAGCTGCTGCAGGAAGCGGGCCTGGCGTTGATCCCCGATAAGCCTGCCACTCAGTGTATTTCAGACGGCAAGTTAAATGAGGGCCACACATTGGACATGGATCTTGTTTTTCTCTTTGACAACAGTAAAATCACCTATGAGACTCAGATCTCCCCACGGCCCCAACCTGAAAGTGTCAGCTGTATCCTTCAAGAGCCCAAGAGGAATCTCGCCTTCTTCCAGCTGAGGAAGGTGTGGGGCCAGGTCTGGCACAGCATCCAGACCCTGAAGGAAGATTGCAACCGGCTGCAGCAGGGACAGCGAGCCGCCATGATGAATCTCCTCCGAAACAACAGCTGCCTCTCCAAAATGAAGAATTCCATGGCTTCCATGTCTCAGCAGCTCAAGGCCAAGTTGGATTTCTTCAAAACCAGCATCCAGATTGACCTGGAGAAGTACAGCGAGCAAACCGAGTTTGGGATCACATCAGATAAACTGCTGCTGGCCTGGAGGGAAATGGAGCAGGCTGTGGAGCTCTGTGGGCGGGAGAACGAAGTGAAACTCCTGGTAGAACGGATGATGGCTCTGCAGACCGACATTGTGGACTTACAGAGGAGCCCCATGGGCCGGAAGCAGGGGGGAACGCTGGACGACCTAGAGGAGCAAGCAAGGGAGCTGTACAGGAGACTAAGGGAAAAACCTCGAGACCAGCGAACTGAGGGTGACAGTCAGGAAATGGTACGGCTGCTGCTTCAGGCAATTCAGAGCTTCGAGAAGAAAGTGCGAGTGATCTATACGCAGCTCAGTAAAACTGTGGTTTGCAAGCAGAAGGCGCTGGAACTGTTGCCCAAGGTGGAAGAGGTGGTGAGCTTAATGAATGAGGATGAGAAGACTGTTGTCCGGCTGCAGGAGAAGCGGCAGAAGGAGCTCTGGAATCTCCTGAAGATTGCTTGTAGCAAGGTCCGTGGTCCTGTCAGTGGAAGCCCGGATAGCATGAATGCCTCTCGACTTAGCCAGCCTGGGCAGCTGATGTCTCAGCCCTCCACGGCCTCCAACAGCTTACCTGAGCCAGCCAAGAAGAGTGAAGAACTGGTGGCTGAAGCACATAACCTCTGCACCCTGCTAGAAAATGCCATACAGGACACTGTGAGGGAACAAGACCAGAGTTTCACGGCCCTAGACTGGAGCTGGTTACAGACGGAAGAAGAAGAGCACAGCTGCCTGGAGC AGGCCTCATGAHuman IκB CDS (SEQ ID NO: 12)ATGTTCCAGGCGGCCGAGCGCCCCCAGGAGTGGGCCATGGAGGGCCCCCGCGACGGGCTGAAGAAGGAGCGGCTACTGGACGACCGCCACGACAGCGGCCTGGACTCCATGAAAGACGAGGAGTACGAGCAGATGGTCAAGGAGCTGCAGGAGATCCGCCTCGAGCCGCAGGAGGTGCCGCGCGGCTCGGAGCCCTGGAAGCAGCAGCTCACCGAGGACGGGGACTCGTTCCTGCACTTGGCCATCATCCATGAAGAAAAGGCACTGACCATGGAAGTGATCCGCCAGGTGAAGGGAGACCTGGCCTTCCTCAACTTCCAGAACAACCTGCAGCAGACTCCACTCCACTTGGCTGTGATCACCAACCAGCCAGAAATTGCTGAGGCACTTCTGGGAGCTGGCTGTGATCCTGAGCTCCGAGACTTTCGAGGAAATACCCCCCTACACCTTGCCTGTGAGCAGGGCTGCCTGGCCAGCGTGGGAGTCCTGACTCAGTCCTGCACCACCCCGCACCTCCACTCCATCCTGAAGGCTACCAACTACAATGGCCACACGTGTCTACACTTAGCCTCTATCCATGGCTACCTGGGCATCGTGGAGCTTTTGGTGTCCTTGGGTGCTGATGTCAATGCTCAGGAGCCCTGTAATGGCCGGACTGCCCTTCACCTCGCAGTGGACCTGCAAAATCCTGACCTGGTGTCACTCCTGTTGAAGTGTGGGGCTGATGTCAACAGAGTTACCTACCAGGGCTATTCTCCCTACCAGCTCACCTGGGGCCGCCCAAGCACCCGGATACAGCAGCAGCTGGGCCAGCTGACACTAGAAAACCTTCAGATGCTGCCAGAGAGTGAGGATGAGGAGAGCTATGACACAGAGTCAGAGTTCACGGAGTTCACAGAGGACGAGCTGCCCTATGATGACTGTGTGTTTGGAGGCCAGCGTCTGACGTT ATGA Human IRAK CDS (SEQ ID NO: 13)ATGGCCGGGGGGCCGGGCCCGGGGGAGCCCGCAGCCCCCGGCGCCCAGCACTTCTTGTACGAGGTGCCGCCCTGGGTCATGTGCCGCTTCTACAAAGTGATGGACGCCCTGGAGCCCGCCGACTGGTGCCAGTTCGCCGCCCTGATCGTGCGCGACCAGACCGAGCTGCGGCTGTGCGAGCGCTCCGGGCAGCGCACGGCCAGCGTCCTGTGGCCCTGGATCAACCGCAACGCCCGTGTGGCCGACCTCGTGCACATCCTCACGCACCTGCAGCTGCTCCGTGCGCGGGACATCATCACAGCCTGGCACCCTCCCGCCCCGCTTCCGTCCCCAGGCACCACTGCCCCGAGGCCCAGCAGCATCCCTGCACCCGCCGAGGCCGAGGCCTGGAGCCCCCGGAAGTTGCCATCCTCAGCCTCCACCTTCCTCTCCCCAGCTTTTCCAGGCTCCCAGACCCATTCAGGGCCTGAGCTCGGCCTGGTCCCAAGCCCTGCTTCCCTGTGGCCTCCACCGCCATCTCCAGCCCCTTCTTCTACCAAGCCAGGCCCAGAGAGCTCAGTGTCCCTCCTGCAGGGAGCCCGCCCCTTTCCGTTTTGCTGGCCCCTCTGTGAGATTTCCCGGGGCACCCACAACTTCTCGGAGGAGCTCAAGATCGGGGAGGGTGGCTTTGGGTGCGTGTACCGGGCGGTGATGAGGAACACGGTGTATGCTGTGAAGAGGCTGAAGGAGAACGCTGACCTGGAGTGGACTGCAGTGAAGCAGAGCTTCCTGACCGAGGTGGAGCAGCTGTCCAGGTTTCGTCACCCAAACATTGTGGACTTTGCTGGCTACTGTGCTCAGAACGGCTTCTACTGCCTGGTGTACGGCTTCCTGCCCAACGGCTCCCTGGAGGACCGTCTCCACTGCCAGACCCAGGCCTGCCCACCTCTCTCCTGGCCTCAGCGACTGGACATCCTTCTGGGTACAGCCCGGGCAATTCAGTTTCTACATCAGGACAGCCCCAGCCTCATCCATGGAGACATCAAGAGTTCCAACGTCCTTCTGGATGAGAGGCTGACACCCAAGCTGGGAGACTTTGGCCTGGCCCGGTTCAGCCGCTTTGCCGGGTCCAGCCCCAGCCAGAGCAGCATGGTGGCCCGGACACAGACAGTGCGGGGCACCCTGGCCTACCTGCCCGAGGAGTACATCAAGACGGGAAGGCTGGCTGTGGACACGGACACCTTCAGCTTTGGGGTGGTAGTGCTAGAGACCTTGGCTGGTCAGAGGGCTGTGAAGACGCACGGTGCCAGGACCAAGTATCTGAAAGACCTGGTGGAAGAGGAGGCTGAGGAGGCTGGAGTGGCTTTGAGAAGCACCCAGAGCACACTGCAAGCAGGTCTGGCTGCAGATGCCTGGGCTGCTCCCATCGCCATGCAGATCTACAAGAAGCACCTGGACCCCAGGCCCGGGCCCTGCCCACCTGAGCTGGGCCTGGGCCTGGGCCAGCTGGCCTGCTGCTGCCTGCACCGCCGGGCCAAAAGGAGGCCTCCTATGACCCAGGTGTACGAGAGGCTAGAGAAGCTGCAGGCAGTGGTGGCGGGGGTGCCCGGGCATTCGGAGGCCGCCAGCTGCATCCCCCCTTCCCCGCAGGAGAACTCCTACGTGTCCAGCACTGGCAGAGCCCACAGTGGGGCTGCTCCATGGCAGCCCCTGGCAGCGCCATCAGGAGCCAGTGCCCAGGCAGCAGAGCAGCTGCAGAGAGGCCCCAACCAGCCCGTGGAGAGTGACGAGAGCCTAGGCGGCCTCTCTGCTGCCCTGCGCTCCTGGCACTTGACTCCAAGCTGCCCTCTGGACCCAGCACCCCTCAGGGAGGCCGGCTGTCCTCAGGGGGACACGGCAGGAGAATCGAGCTGGGGGAGTGGCCCAGGATCCCGGCCCACAGCCGTGGAAGGACTGGCCCTTGGCAGCTCTGCATCATCGTCGTCAGAGCCACCGCAGATTATCATCAACCCTGCCCGACAGAAGATGGTCCAGAAGCTGGCCCTGTACGAGGATGGGGCCCTGGACAGCCTGCAGCTGCTGTCGTCCAGCTCCCTCCCAGGCTTGGGCCTGGAACAGGACAGGCAGGGGCCCGAAGAAAGTGATGAATTTCAGAGCTGA Human JNK CDS (SEQ ID NO: 14)ATGAGCAGAAGCAAGCGTGACAACAATTTTTATAGTGTAGAGATTGGAGATTCTACATTCACAGTCCTGAAACGATATCAGAATTTAAAACCTATAGGCTCAGGAGCTCAAGGAATAGTATGCGCAGCTTATGATGCCATTCTTGAAAGAAATGTTGCAATCAAGAAGCTAAGCCGACCATTTCAGAATCAGACTCATGCCAAGCGGGCCTACAGAGAGCTAGTTCTTATGAAATGTGTTAATCACAAAAATATAATTGGCCTTTTGAATGTTTTCACACCACAGAAATCCCTAGAAGAATTTCAAGATGTTTACATAGTCATGGAGCTCATGGATGCAAATCTTTGCCAAGTGATTCAGATGGAGCTAGATCATGAAAGAATGTCCTACCTTCTCTATCAGATGCTGTGTGGAATCAAGCACCTTCATTCTGCTGGAATTATTCATCGGGACTTAAAGCCCAGTAATATAGTAGTAAAATCTGATTGCACTTTGAAGATTCTTGACTTCGGTCTGGCCAGGACTGCAGGAACGAGTTTTATGATGACGCCTTATGTAGTGACTCGCTACTACAGAGCACCCGAGGTCATCCTTGGCATGGGCTACAAGGAAAACGTTGACATTTGGTCAGTTGGGTGCATCATGGGAGAAATGATCAAAGGTGGTGTTTTGTTCCCAGGTACAGATCATATTGATCAGTGGAATAAAGTTATTGAACAGCTTGGAACACCATGTCCTGAATTCATGAAGAAACTGCAACCAACAGTAAGGACTTACGTTGAAAACAGACCTAAATATGCTGGATATAGCTTTGAGAAACTCTTCCCTGATGTCCTTTTCCCAGCTGACTCAGAACACAACAAACTTAAAGCCAGTCAGGCAAGGGATTTGTTATCCAAAATGCTGGTAATAGATGCATCTAAAAGGATCTCTGTAGATGAAGCTCTCCAACACCCGTACATCAAGTCTGGTATGATCCTTCTGAAGCAGAAGCTCCACCACCAAAGATCCCTGACAAGCAGTTAGATGAAAGGGAACACACAATAGAAGAGTGGAAAGAATTGATATATAAGGAAGTTATGGACTTGGAGGAGAGAACCAAGAATGGAGTTATACGGGGGCAGCCCTCTCCTTTAGGTGCAGCAGTGATCAATGGCTCTCAGCATCCATCATCATCGTCGTCTGTCAATGATGTGTCTTCAATGTCAACAGATCCGACTTTGGCCTCTGATACAGACAGCAGTCTAGAAGCAGCAGCTGGGCCTCTGGGCTGC TGTAGATGAHuman LBP CDS (SEQ ID NO: 15)ATGGGGGCCTTGGCCAGAGCCCTGCCGTCCATACTGCTGGCATTGCTGCTTACGTCCACCCCAGAGGCTCTGGGTGCCAACCCCGGCTTGGTCGCCAGGATCACCGACAAGGGACTGCAGTATGCGGCCCAGGAGGGGCTATTAGCTCTGCAGAGTGAGCTGCTCAGGATCACGCTGCCTGACTTCACCGGGGACTTGAGGATCCCCCACGTCGGCCGTGGGCGCTATGAGTTCCACAGCCTGAACATCCACAGCTGTGAGCTGCTTCACTCTGCGCTGAGGCCTGTCCCTGGCCAGGGCCTGAGTCTCAGCATCTCCGACTCCTCCATCCGGGTCCAGGGCAGGTGGAAGGTGCGCAAGTCATTCTTCAAACTACAGGGCTCCTTTGATGTCAGTGTCAAGGGCATCAGCATTTCGGTCAACCTCCTGTTGGGCAGCGAGTCCTCCGGGAGGCCCACAGTTACTGCCTCCAGCTGCAGCAGTGACATCGCTGACGTGGAGGTGGACATGTCGGGAGACTTGGGGTGGCTGTTGAACCTCTTCCACAACCAGATTGAGTCCAAGTTCCAGAAAGTACTGGAGAGCAGGATTTGCGAAATGATCCAGAAATCGGTGTCCTCCGATCTACAGCCTTATCTCCAAACTCTGCCAGTTACAACAGAGATTGACAGTTTCGCCGACATTGATTATAGCTTAGTGGAAGCCCCTCGGGCAACAGCCCAGATGCTGGAGGTGATGTTTAAGGGTGAAATCTTTCATCGTAACCACCGTTCTCCAGTTACCCTCCTTGCTGCAGTCATGAGCCTTCCTGAGGAACACAACAAAATGGTCTACTTTGCCATCTCGGATTATGTCTTCAACACGGCCAGCCTGGTTTATCATGAGGAAGGATATCTGAACTTCTCCATCACAGATGACATGATACCGCCTGACTCTAATATCCGACTGACCACCAAGTCCTTCCGACCCTTCGTCCCACGGTTAGCCAGGCTCTACCCCAACATGAACCTGGAACTCCAGGGATCAGTGCCCTCTGCTCCGCTCCTGAACTTCAGCCCTGGGAATCTGTCTGTGGACCCCTATATGGAGATAGATGCCTTTGTGCTCCTGCCCAGCTCCAGCAAGGAGCCTGTCTTCCGGCTCAGTGTGGCCACTAATGTGTCCGCCACCTTGACCTTCAATACCAGCAAGATCACTGGGTTCCTGAAGCCAGGAAAGGTAAAAGTGGAACTGAAAGAATCCAAAGTTGGACTATTCAATGCAGAGCTGTTGGAAGCGCTCCTCAACTATTACATCCTTAACACCCTCTACCCCAAGTTCAATGATAAGTTGGCCGAAGGCTTCCCCCTTCCTCTGCTGAAGCGTGTTCAGCTCTACGACCTTGGGCTGCAGATCCATAAGGACTTCCTGTTCTTGGGTGCCAATGTCCAATACATGAGAGTTTGA Human MEK1 CDS (SEQ ID NO: 16)ATGCCCAAGAAGAAGCCGACGCCCATCCAGCTGAACCCGGCCCCCGACGGCTCTGCAGTTAACGGGACCAGCTCTGCGGAGACCAACTTGGAGGCCTTGCAGAAGAAGCTGGAGGAGCTAGAGCTTGATGAGCAGCAGCGAAAGCGCCTTGAGGCCTTTCTTACCCAGAAGCAGAAGGTGGGAGAACTGAAGGATGACGACTTTGAGAAGATCAGTGAGCTGGGGGCTGGCAATGGCGGTGTGGTGTTCAAGGTCTCCCACAAGCCTTCTGGCCTGGTCATGGCCAGAAAGCTAATTCATCTGGAGATCAAACCCGCAATCCGGAACCAGATCATAAGGGAGCTGCAGGTTCTGCATGAGTGCAACTCTCCGTACATCGTGGGCTTCTATGGTGCGTTCTACAGCGATGGCGAGATCAGTATCTGCATGGAGCACATGGATGGAGGTTCTCTGGATCAAGTCCTGAAGAAAGCTGGAAGAATTCCTGAACAAATTTTAGGAAAAGTTAGCATTGCTGTAATAAAAGGCCTGACATATCTGAGGGAGAAGCACAAGATCATGCACAGAGATGTCAAGCCCTCCAACATCCTAGTCAACTCCCGTGGGGAGATCAAGCTCTGTGACTTTGGGGTCAGCGGGCAGCTCATCGACTCCATGGCCAACTCCTTCGTGGGCACAAGGTCCTACATGTCGCCAGAAAGACTCCAGGGGACTCATTACTCTGTGCAGTCAGACATCTGGAGCATGGGACTGTCTCTGGTAGAGATGGCGGTTGGGAGGTATCCCATCCTCCTCCAGATGCCAAGGAGCTGGAGCTGATGTTTGGGTGCCAGGTGGAAGGAGATGCGGCTGAGACCCCACCCAGGCCAAGGACCCCCGGGAGGCCCCTTAGCTCATACGGAATGGACAGCCGACCTCCCATGGCAATTTTTGAGTTGTTGGATTACATAGTCAACGAGCCTCCTCCAAAACTGCCCAGTGGAGTGTTCAGTCTGGAATTTCAAGATTTTGTGAATAAATGCTTAATAAAAAACCCCGCAGAGAGAGCAGATTTGAAGCAACTCATGGTTCATGCTTTTATCAAGAGATCTGATGCTGAGGAAGTGGATTTTGCAGGTTGGCTCTGCTCCACCATCGGCCTTAACCAGCCCAGC ACACCAACCCATGCTGCTGGC GTCTAAHuman MEK2 CDS (SEQ ID NO: 17)ATGCTGGCCCGGAGGAAGCCGGTGCTGCCGGCGCTCACCATCAACCCTACCATCGCCGAGGGCCCATCCCCTACCAGCGAGGGCGCCTCCGAGGCAAACCTGGTGGACCTGCAGAAGAAGCTGGAGGAGCTGGAACTTGACGAGCAGCAGAAGAAGCGGCTGGAAGCCTTTCTCACCCAGAAAGCCAAGGTCGGCGAACTCAAAGACGATGACTTCGAAAGGATCTCAGAGCTGGGCGCGGGCAACGGCGGGGTGGTCACCAAAGTCCAGCACAGACCCTCGGGCCTCATCATGGCCAGGAAGCTGATCCACCTTGAGATCAAGCCGGCCATCCGGAACCAGATCATCCGCGAGCTGCAGGTCCTGCACGAATGCAACTCGCCGTACATCGTGGGCTTCTACGGGGCCTTCTACAGTGACGGGGAGATCAGCATTTGCATGGAACACATGGACGGCGGCTCCCTGGACCAGGTGCTGAAAGAGGCCAAGAGGATTCCCGAGGAGATCCTGGGGAAAGTCAGCATCGCGGTTCTCCGGGGCTTGGCGTACCTCCGAGAGAAGCACCAGATCATGCACCGAGATGTGAAGCCCTCCAACATCCTCGTGAACTCTAGAGGGGAGATCAAGCTGTGTGACTTCGGGGTGAGCGGCCAGCTCATCGACTCCATGGCCAACTCCTTCGTGGGCACGCGCTCCTACATGGCTCCGGAGCGGTTGCAGGGCACACATTACTCGGTGCAGTCGGACATCTGGAGCATGGGCCTGTCCCTGGTGGAGCTGGCCGTCGGAAGGTACCCCATCCCCCCGCCCGACGCCAAAGAGCTGGAGGCCATCTTTGGCCGGCCCGTGGTCGACGGGGAAGAAGGAGAGCCTCACAGCATCTCGCCTCGGCCGAGGCCCCCCGGGCGCCCCGTCAGCGGTCACGGGATGGATAGCCGGCCTGCCATGGCCATCTTTGAACTCCTGGACTATATTGTGAACGAGCCACCTCCTAAGCTGCCCAACGGTGTGTTCACCCCCGACTTCCAGGAGTTTGTCAATAAATGCCTCATCAAGAACCCAGCGGAGCGGGCGGACCTGAAGATGCTCACAAACCACACCTTCATCAAGCGGTCCGAGGTGGAAGAAGTGGATTTTGCCGGCTGGTTGTGTAAAACCCTGCGGCTGAACCAGCCCGGCACACCCACGCGCACCGCCGTGTGA Human MEK3 CDS (SEQ ID NO: 18)ATGTCCAAGCCACCCGCACCCAACCCCACACCCCCCCGGAACCTGGACTCCCGGACCTTCATCACCATTGGAGACAGAAACTTTGAGGTGGAGGCTGATGACTTGGTGACCATCTCAGAACTGGGCCGTGGAGCCTATGGGGTGGTAGAGAAGGTGCGGCACGCCCAGAGCGGCACCATCATGGCCGTGAAGCGGATCCGGGCCACCGTGAACTCACAGGAGCAGAAGCGGCTGCTCATGGACCTGGACATCAACATGCGCACGGTCGACTGTTTCTACACTGTCACCTTCTACGGGGCACTATTCAGAGAGGGAGACGTGTGGATCTGCATGGAGCTCATGGACACATCCTTGGACAAGTTCTACCGGAAGGTGCTGGATAAAAACATGACAATTCCAGAGGACATCCTTGGGGAGATTGCTGTGTCTATCGTGCGGGCCCTGGAGCATCTGCACAGCAAGCTGTCGGTGATCCACAGAGATGTGAAGCCCTCCAATGTCCTTATCAACAAGGAGGGCCATGTGAAGATGTGTGACTTTGGCATCAGTGGCTACTTGGTGGACTCTGTGGCCAAGACGATGGATGCCGGCTGCAAGCCCTACATGGCCCCTGAGAGGATCAACCCAGAGCTGAACCAGAAGGGCTACAATGTCAAGTCCGACGTCTGGAGCCTGGGCATCACCATGATTGAGATGGCCATCCTGCGGTTCCCTTACGAGTCCTGGGGGACCCCGTTCCAGCAGCTGAAGCAGGTGGTGGAGGAGCCGTCCCCCCAGCTCCCAGCCGACCGTTTCTCCCCCGAGTTTGTGGACTTCACTGCTCAGTGCCTGAGGAAGAACCCCGCAGAGCGTATGAGCTACCTGGAGCTGATGGAGCACCCCTTCTTCACCTTGCACAAAACCAAGAAGACGGACATTGCTGCCTTCGTGAAGGAGATCCTGGGAGAAGACTCATAG Human MEK6 CDS (SEQ ID NO: 19)ATGTCTCAGTCGAAAGGCAAGAAGCGAAACCCTGGCCTTAAAATTCCAAAAGAAGCATTTGAACAACCTCAGACCAGTTCCACACCACCTCGAGATTTAGACTCCAAGGCTTGCATTTCTATTGGAAATCAGAACTTTGAGGTGAAGGCAGATGACCTGGAGCCTATAATGGAACTGGGACGAGGTGCGTACGGGGTGGTGGAGAAGATGCGGCACGTGCCCAGCGGGCAGATCATGGCAGTGAAGCGGATCCGAGCCACAGTAAATAGCCAGGAACAGAAACGGCTACTGATGGATTTGGATATTTCCATGAGGACGGTGGACTGTCCATTCACTGTCACCTTTTATGGCGCACTGTTTCGGGAGGGTGATGTGTGGATCTGCATGGAGCTCATGGATACATCACTAGATAAATTCTACAAACAAGTTATTGATAAAGGCCAGACAATTCCAGAGGACATCTTAGGGAAAATAGCAGTTTCTATTGTAAAAGCATTAGAACATTTACATAGTAAGCTGTCTGTCATTCACAGAGACGTCAAGCCTTCTAATGTACTCATCAATGCTCTCGGTCAAGTGAAGATGTGCGATTTTGGAATCAGTGGCTACTTGGTGGACTCTGTTGCTAAAACAATTGATGCAGGTTGCAAACCATACATGGCCCCTGAAAGAATAAACCCAGAGCTCAACCAGAAGGGATACAGTGTGAAGTCTGACATTTGGAGTCTGGGCATCACGATGATTGAGTTGGCCATCCTTCGATTTCCCTATGATTCATGGGGAACTCCATTTCAGCAGCTCAAACAGGTGGTAGAGGAGCCATCGCCACAACTCCCAGCAGACAAGTTCTCTGCAGAGTTTGTTGACTTTACCTCACAGTGCTTAAAGAAGAATTCCAAAGAACGGCCTACATACCCAGAGCTAATGCAACATCCATTTTTCACCCTACATGAATCCAAAGGAACAGATGTGGCATCTTTTGTAAAACTGATTCTTGGAGACTAA Human MEKK1 CDS (SEQ ID NO: 20)ATGGCGGCGGCGGCGGGGAATCGCGCCTCGTCGTCGGGATTCCCGGGCGCCAGGGCTACGAGCCCTGAGGCAGGCGGCGGCGGAGGAGCCCTCAAGGCGAGCAGCGCGCCCGCGGCTGCCGCGGGACTGCTGCGGGAGGCGGGCAGCGGGGGCCGCGAGCGGGCGGACTGGCGGCGGCGGCAGCTGCGCAAAGTGCGGAGTGTGGAGCTGGACCAGCTGCCTGAGCAGCCGCTCTTCCTTGCCGCCTCACCGCCGGCCTCCTCGACTTCCCCGTCGCCGGAGCCCGCGGACGCAGCGGGGAGTGGGACCGGCTTCCAGCCTGTGGCGGTGCCGCCGCCCCACGGAGCCGCGAGCCGCGGCGGCGCCCACCTTACCGAGTCGGTGGCGGCGCCGGACAGCGGCGCCTCGAGTCCCGCAGCGGCCGAGCCCGGGGAGAAGCGGGCGCCCGCCGCCGAGCCGTCTCCTGCAGCGGCCCCCGCCGGTCGTGAGATGGAGAATAAAGAAACTCTCAAAGGGTTGCACAAGATGGATGATCGTCCAGAGGAACGAATGATCAGGGAGAAACTGAAGGCAACCTGTATGCCAGCCTGGAAGCACGAATGGTTGGAAAGGAGAAATAGGCGAGGGCCTGTGGTGGTAAAACCAATCCCAGTTAAAGGAGATGGATCTGAAATGAATCACTTAGCAGCTGAGTCTCCAGGAGAGGTCCAGGCAAGTGCGGCTTCACCAGCTTCCAAAGGCCGACGCAGTCCTTCTCCTGGCAACTCCCCATCAGGTCGCACAGTGAAATCAGAATCTCCAGGAGTAAGGAGAAAAAGAGTTTCCCCAGTGCCTTTTCAGAGTGGCAGAATCACACCACCCCGAAGAGCCCCTTCACCAGATGGCTTCTCACCATATAGCCCTGAGGAAACAAACCGCCGTGTTAACAAAGTGATGCGGGCCAGACTGTACTTACTGCAGCAGATAGGGCCTAACTCTTTCCTGATTGGAGGAGACAGCCCAGACAATAAATACCGGGTGTTTATTGGGCCTCAGAACTGCAGCTGTGCACGTGGAACATTCTGTATTCATCTGCTATTTGTGATGCTCCGGGTGTTTCAACTAGAACCTTCAGACCCAATGTTATGGAGAAAAACTTTAAAGAATTTTGAGGTTGAGAGTTTGTTCCAGAAATATCACAGTAGGCGTAGCTCAAGGATCAAAGCTCCATCTCGTAACACCATCCAGAAGTTTGTTTCACGCATGTCAAATTCTCATACATTGTCATCATCTAGTACTTCTACGTCTAGTTCAGAAAACAGCATAAAGGATGAAGAGGAACAGATGTGTCCTATTTGCTTGTTGGGCATGCTTGATGAAGAAAGTCTTACAGTGTGTGAAGACGGCTGCAGGAACAAGCTGCACCACCACTGCATGTCAATTTGGGCAGAAGAGTGTAGAAGAAATAGAGAACCTTTAATATGTCCCCTTTGTAGATCTAAGTGGAGATCTCATGATTTCTACAGCCACGAGTTGTCAAGTCCTGTGGATTCCCCTTCTTCCCTCAGAGCTGCACAGCAGCAAACCGTACAGCAGCAGCCTTTGGCTGGATCACGAAGGAATCAAGAGAGCAATTTTAACCTTACTCATTATGGAACTCAGCAAATCCCTCCTGCTTACAAAGATTTAGCTGAGCCATGGATTCAGGTGTTTGGAATGGAACTCGTTGGCTGCTTATTTTCTAGAAACTGGAATGTGAGAGAGATGGCCCTCAGGCGTCTTTCCCATGATGTCAGTGGGGCCCTGCTGTTGGCAAATGGGGAGAGCACTGGAAATTCTGGGGGCAGCAGTGGAAGCAGCCCGAGTGGGGGAGCCACCAGTGGGTCTTCCCAGACCAGTATCTCAGGAGATGTGGTGGAGGCATGCTGCAGCGTTCTGTCAATGGTCTGTGCTGACCCTGTCTACAAAGTGTACGTTGCTGCTTTAAAAACATTGAGAGCCATGCTGGTATATACTCCTTGCCACAGTTTAGCGGAAAGAATCAAACTTCAGAGACTTCTCCAGCCAGTTGTAGACACCATCCTAGTCAAATGTGCAGATGCCAATAGCCGCACAAGTCAGCTGTCCATATCAACACTGTTGGAACTGTGCAAAGGCCAAGCAGGAGAGTTGGCAGTTGGCAGAGAAATACTAAAAGCTGGATCCATTGGTATTGGTGGTGTTGATTATGTCTTAAATTGTATTCTTGGAAACCAAACTGAATCAAACAATTGGCAAGAACTTCTTGGCCGCCTTTGTCTTATAGATAGACTGTTGTTGGAATTTCCTGCTGAATTTTATCCTCATATTGTCAGTACTGATGTTTCACAAGCTGAGCCTGTTGAAATCAGGTATAAGAAGCTGCTGTCCCTCTTAACCTTTGCTTTGCAGTCCATTGATAATTCCCACTCAATGGTTGGCAAACTTTCCAGAAGGATCTACTTGAGTTCTGCAAGAATGGTTACTACAGTACCCCATGTGTTTTCAAAACTGTTAGAAATGCTGAGTGTTTCCAGTTCCACTCACTTCACCAGGATGCGTCGCCGTTTGATGGCTATTGCAGATGAGGTGGAAATTGCCGAAGCCATCCAGTTGGGCGTAGAAGACACTTTGGATGGTCAACAGGACAGCTTCTTGCAGGCATCTGTTCCCAACAACTATCTGGAAACCACAGAGAACAGTTCCCCTGAGTGCACAGTCCATTTAGAGAAAACTGGAAAAGGATTATGTGCTACAAAATTGAGTGCCAGTTCAGAGGACATTTCTGAGAGACTGGCCAGCATTTCAGTAGGACCTTCTAGTTCAACAACAACAACAACAACAACAACAGAGCAACCAAAGCCAATGGTTCAAACAAAAGGCAGACCCCACAGTCAGTGTTTGAACTCCTCTCCTTTATCTCATCATTCCCAATTAATGTTTCCAGCCTTGTCAACCCCTTCTTCTTCTACCCCATCTGTACCAGCTGGCACTGCAACAGATGTCTCTAAGCATAGACTTCAGGGATTCATTCCCTGCAGAATACCTTCTGCATCTCCTCAAACACAGCGCAAGTTTTCTCTACAATTCCACAGAAACTGTCCTGAAAACAAAGACTCAGATAAACTTTCCCCAGTCTTTACTCAGTCAAGACCCTTGCCCTCCAGTAACATACACAGGCCAAAGCCATCTAGACCTACCCCAGGTAATACAAGTAAACAGGGAGATCCCTCAAAAAATAGCATGACACTTGATCTGAACAGTAGTTCCAAATGTGATGACAGCTTTGGCTGTAGCAGCAATAGTAGTAATGCTGTTATACCCAGTGACGAGACAGTGTTCACCCCAGTAGAGGAGAAATGCAGATTAGATGTCAATACAGAGCTCAACTCCAGTATTGAGGACCTTCTTGAAGCATCTATGCCTTCAAGTGATACAACAGTAACTTTTAAGTCAGAAGTTGCTGTCCTGTCTCCTGAAAAGGCTGAAAATGATGATACCTACAAAGATGATGTGAATCATAATCAAAAGTGCAAAGAGAAGATGGAAGCTGAAGAAGAAGAAGCTTTAGCAATTGCCATGGCAATGTCAGCGTCTCAGGATGCCCTCCCCATAGTTCCTCAGCTGCAGGTTGAAAATGGAGAAGATATCATCATTATTCAACAGGATACACCAGAGACTCTACCAGGACATACCAAAGCAAAACAACCGTATAGAGAAGACACTGAATGGCTGAAAGGTCAACAGATAGGCCTTGGAGCATTTTCTTCTTGTTATCAGGCTCAAGATGTGGGAACTGGAACTTTAATGGCTGTTAAACAGGTGACTTATGTCAGAAACACATCTTCTGAGCAAGAAGAAGTAGTAGAAGCACTAAGAGAAGAGATAAGAATGATGAGCCATCTGAATCATCCAAACATCATTAGGATGTTGGGAGCCACGTGTGAGAAGAGCAATTACAATCTCTTCATTGAATGGATGGCAGGGGGATCGGTGGCTCATTTGCTGAGTAAATATGGAGCCTTCAAAGAATCAGTAGTTATTAACTACACTGAACAGTTACTCCGTGGCCTTTCGTATCTCCATGAAAACCAAATCATTCACAGAGATGTCAAAGGTGCCAATTTGCTAATTGACAGCACTGGTCAGAGACTAAGAATTGCAGATTTTGGAGCTGCAGCCAGGTTGGCATCAAAAGGAACTGGTGCAGGAGAGTTTCAGGGACAATTACTGGGGACAATTGCATTTATGGCACCTGAGGTACTAAGAGGTCAACAGTATGGAAGGAGCTGTGATGTATGGAGTGTTGGCTGTGCTATTATAGAAATGGCTTGTGCAAAACCACCATGGAATGCAGAAAAACACTCCAATCATCTTGCTTTGATATTTAAGATTGCTAGTGCAACTACTGCTCCATCGATCCCTTCACATTTGTCTCCTGGTTTACGAGATGTGGCTCTTCGTTGTTTAGAACTTCAACCTCAGGACAGACCTCCATCAAGAGAGCTACTGAAGCATCCAGTCTTTCGTACTACATGGTAG Human MEKK 3 CDS (SEQ ID NO: 21)ATGGACGAACAGGAGGCATTGAACTCAATCATGAACGATCTGGTGGCCCTCCAGATGAACCGACGTCACCGGATGCCTGGATATGAGACCATGAAGAACAAAGACACAGGTCACTCAAATAGGCAGAAAAAACACAACAGCAGCAGCTCAGCCCTTCTGAACAGCCCCACAGTAACAACAAGCTCATGTGCAGGGGCCAGTGAGAAAAAGAAATTTTTGAGTGACGTCAGAATCAAGTTCGAGCACAACGGGGAGAGGCGAATTATAGCGTTCAGCCGGCCTGTGAAATATGAAGATGTGGAGCACAAGGTGACAACAGTATTTGGACAACCTCTTGATCTACATTACATGAACAATGAGCTCTCCATCCTGCTGAAAAACCAAGATGATCTTGATAAAGCAATTGACATTTTAGATAGAAGCTCAAGCATGAAAAGCCTTAGGATATTGCTGTTGTCCCAGGACAGAAACCATAACAGTTCCTCTCCCCACTCTGGGGTGTCCAGACAGGTGCGGATCAAGGCTTCCCAGTCCGCAGGGGATATAAATACTATCTACCAGCCCCCCGAGCCCAGAAGCAGGCACCTCTCTGTCAGCTCCCAGAACCCTGGCCGAAGCTCACCTCCCCCTGGCTATGTTCCTGAGCGGCAGCAGCACATTGCCCGGCAGGGGTCCTACACCAGCATCAACAGTGAGGGGGAGTTCATCCCAGAGACCAGCGAGCAGTGCATGCTGGATCCCCTGAGCAGTGCAGAAAATTCCTTGTCTGGAAGCTGCCAATCCTTGGACAGGTCAGCAGACAGCCCATCCTTCCGGAAATCACGAATGTCCCGTGCCCAGAGCTTCCCTGACAACAGACAGGAATACTCAGATCGGGAAACTCAGCTTTATGACAAAGGGGTCAAAGGTGGAACCTACCCCCGGCGCTACCACGTGTCTGTGCACCACAAGGACTACAGTGATGGCAGAAGAACATTTCCCCGAATACGGCGTCATCAAGGCAACTTGTTCACCCTGGTGCCCTCCAGCCGCTCCCTGAGCACAAATGGCGAGAACATGGGTCTGGCTGTGCAATACCTGGACCCCCGTGGGCGCCTGCGGAGTGCGGACAGCGAGAATGCCCTCTCTGTGCAGGAGAGGAATGTGCCAACCAAGTCTCCCAGTGCCCCCATCAACTGGCGCCGGGGAAAGCTCCTGGGCCAGGGTGCCTTCGGCAGGGTCTATTTGTGCTATGACGTGGACACGGGACGTGAACTTGCTTCCAAGCAGGTCCAATTTGATCCAGACAGTCCTGAGACAAGCAAGGAGGTGAGTGCTCTGGAGTGCGAGATCCAGTTGCTAAAGAACTTGCAGCATGAGCGCATCGTGCAGTACTATGGCTGTCTGCGGGACCGCGCTGAGAAGACCCTGACCATCTTCATGGAGTACATGCCAGGGGGCTCGGTGAAAGACCAGTTGAAGGCTTACGGTGCTCTGACAGAGAGCGTGACCCGAAAGTACACGCGGCAGATCCTGGAGGGCATGTCCTACCTGCACAGCAACATGATTGTTCACCGGGACATTAAGGGAGCCAACATCCTCCGAGACTCTGCTGGGAATGTAAAGCTGGGGGACTTTGGGGCCAGCAAACGCCTGCAGACGATCTGTATGTCGGGGACGGGCATGCGCTCCGTCACTGGCACACCCTACTGGATGAGCCCTGAGGTGATCAGCGGCGAGGGCTATGGAAGGAAAGCAGACGTGTGGAGCCTGGGCTGCACTGTGGTGGAGATGCTGACAGAGAAACCACCGTGGGCAGAGTATGAAGCTATGGCCGCCATCTTCAAGATTGCCACCCAGCCCACCAATCCTCAGCTGCCCTCCCACATCTCTGAACATGGCCGGGACTTCCTGAGGCGCATTTTTGTGGAGGCTCGCCAGAGACCTTCAGCTGAGGAGCTGCTCACACACCACTTTGCACAGCTCATGTACTGA Human MEKK4 CDS (SEQ ID NO: 22)ATGAGAGAAGCCGCTGCCGCGCTGGTCCCTCCTCCCGCCTTTGCCGTCACGCCTGCCGCCGCCATGGAGGAGCCGCCGCCACCGCCGCCGCCGCCACCACCGCCACCGGAACCCGAGACCGAGTCAGAACCCGAGTGCTGCTTGGCGGCGAGGCAAGAGGGCACATTGGGAGATTCAGCTTGCAAGAGTCCTGAATCTGATCTAGAAGACTTCTCCGATGAAACAAATACAGAGAATCTTTATGGTACCTCTCCCCCCAGCACACCTCGACAGATGAAACGCATGTCAACCAAACATCAGAGGAATAATGTGGGGAGGCCAGCCAGTCGGTCTAATTTGAAAGAAAAAATGAATGCACCAAATCAGCCTCCACATAAAGACACTGGAAAAACAGTGGAGAATGTGGAAGAATACAGCTATAAGCAGGAGAAAAAGATCCGAGCAGCTCTTAGAACAACAGAGCGTGATCATAAAAAAAATGTACAGTGCTCATTCATGTTAGACTCAGTGGGTGGATCTTTGCCAAAAAAATCAATTCCAGATGTGGATCTCAATAAGCCTTACCTCAGCCTTGGCTGTAGCAATGCTAAGCTTCCAGTATCTGTGCCCATGCCTATAGCCAGACCTGCACGCCAGACTTCTAGGACTGACTGTCCAGCAGATCGTTTAAAGTTTTTTGAAACTTTACGACTTTTGCTAAAGCTTACCTCAGTCTCAAAGAAAAAAGACAGGGAGCAAAGAGGACAAGAAAATACGTCTGGTTTCTGGCTTAACCGATCTAACGAACTGATCTGGTTAGAGCTACAAGCCTGGCATGCAGGACGGACAATTAACGACCAGGACTTCTTTTTATATACAGCCCGTCAAGCCATCCCAGATATTATTAATGAAATCCTTACTTTCAAAGTCGACTATGGGAGCTTCGCCTTTGTTAGAGATAGAGCTGGTTTTAATGGTACTTCAGTAGAAGGGCAGTGCAAAGCCACTCCTGGAACAAAGATTGTAGGTTACTCAACACATCATGAGCATCTCCAACGCCAGAGGGTCTCATTTGAGCAGGTAAAACGGATAATGGAGCTGCTAGAGTACATAGAAGCACTTTATCCATCATTGCAGGCTCTTCAGAAGGACTATGAAAAATATGCTGCAAAAGACTTCCAGGACAGGGTGCAGGCACTCTGTTTGTGGTTAAACATCACAAAAGACTTAAATCAGAAATTAAGGATTATGGGCACTGTTTTGGGCATCAAGAATTTATCAGACATTGGCTGGCCAGTGTTTGAAATCCCTTCCCCTCGACCATCCAAAGGTAATGAGCCGGAGTATGAGGGTGATGACACAGAAGGAGAATTAAAGGAGTTGGAAAGTAGTACGGATGAGAGTGAAGAAGAACAAATCTCTGATCCTAGGGTACCGGAAATCAGACAGCCCATAGATAACAGCTTCGACATCCAGTCGCGGGACTGCATATCCAAGAAGCTTGAGAGGCTCGAATCTGAGGATGATTCTCTTGGCTGGGGAGCACCAGACTGGAGCACAGAAGCAGGCTTTAGTAGACATTGTCTGACTTCTATTTATAGACCATTTGTAGACAAAGCACTGAAGCAGATGGGGTTAAGAAAGTTAATTTTAAGACTTCACAAGCTAATGGATGGTTCCTTGCAAAGGGCACGTATAGCATTGGTAAAGAACGATCGTCCAGTGGAGTTTTCTGAATTTCCAGATCCCATGTGGGGTTCAGATTATGTGCAGTTGTCAAGGACACCACCTTCATCTGAGGAGAAATGCAGTGCTGTGTCGTGGGAGGAGCTGAAGGCCATGGATTTACCTTCATTCGAACCTGCCTTCCTAGTTCTCTGCCGAGTCCTTCTGAATGTCATACATGAGTGTCTGAAGTTAAGATTGGAGCAGAGACCTGCTGGAGAACCATCTCTCTTGAGTATTAAGCAGCTGGTGAGAGAGTGTAAGGAGGTCCTGAAGGGCGGCCTGCTGATGAAGCAGTACTACCAGTTCATGCTGCAGGAGGTTCTGGAGGACTTGGAGAAGCCCGACTGCAACATTGACGCTTTTGAAGAGGATCTACATAAAATGCTTATGGTGTATTTTGATTACATGAGAAGCTGGATCCAAATGCTACAGCAATTACCTCAAGCATCGCATAGTTTAAAAAATCTGTTAGAAGAAGAATGGAATTTCACCAAAGAAATAACTCATTACATACGGGGAGGAGAAGCACAGGCCGGGAAGCTTTTCTGTGACATTGCAGGAATGCTGCTGAAATCTACAGGAAGTTTTTTAGAATTTGGCTTACAGGAGAGCTGTGCTGAATTTTGGACTAGTGCGGATGACAGCAGTGCTTCCGACGAAATCAGGAGGTCTGTTATAGAGATCAGTCGAGCCCTGAAGGAGCTCTTCCATGAAGCCAGAGAAAGGGCTTCCAAAGCACTTGGATTTGCTAAAATGTTGAGAAAGGACCTGGAAATAGCAGCAGAATTCAGGCTTTCAGCCCCAGTTAGAGACCTCCTGGATGTTCTGAAATCAAAACAGTATGTCAAGGTGCAAATTCCTGGGTTAGAAAACTTGCAAATGTTTGTTCCAGACACTCTTGCTGAGGAGAAGAGTATTATTTTGCAGTTACTCAATGCAGCTGCAGGAAAGGACTGTTCAAAAGATTCAGATGACGTACTCATCGATGCCTATCTGCTTCTGACCAAGCACGGTGATCGAGCCCGTGATTCAGAGGACAGCTGGGGCACCTGGGAGGCACAGCCTGTCAAAGTCGTGCCTCAGGTGGAGACTGTTGACACCCTGAGAAGCATGCAGGTGGATAATCTTTTACTAGTTGTCATGCAGTCTGCGCATCTCACAATTCAGAGAAAAGCTTTCCAGCAGTCCATTGAGGGACTTATGACTCTGTGCCAGGAGCAGACATCCAGTCAGCCGGTCATCGCCAAAGCTTTGCAGCAGCTGAAGAATGATGCATTGGAGCTATGCAACAGGATAAGCAATGCCATTGACCGCGTGGACCACATGTTCACATCAGAATTTGATGCTGAGGTTGATGAATCTGAATCTGTCACCTTGCAACAGTACTACCGAGAAGCAATGATTCAGGGGTACAATTTTGGATTTGAGTATCATAAAGAAGTTGTTCGTTTGATGTCTGGGGAGTTTAGACAGAAGATAGGAGACAAATATATAAGCTTTGCCCGGAAGTGGATGAATTATGTCCTGACTAAATGTGAGAGTGGTAGAGGTACAAGACCCAGGTGGGCGACTCAAGGATTTGATTTTCTACAAGCAATTGAACCTGCCTTTATTTCAGCTTTACCAGAAGATGACTTCTTGAGTTTACAAGCCTTGATGAATGAATGCATTGGCCATGTCATAGGAAAACCACACAGTCCTGTTACAGGTTTGTACCTTGCCATTCATCGGAACAGCCCCCGTCCTATGAAGGTACCTCGATGCCATAGTGACCCTCCTAACCCACACCTCATTATCCCCACTCCAGAGGGATTCAGCACTCGGAGCATGCCTTCCGACGCGCGGAGCCATGGCAGCCCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGTTGCTGCCAGTCGGCCCAGCCCCTCTGGTGGTGACTCTGTGCTGCCCAAATCCATCAGCAGTGCCCATGATACCAGGGGTTCCAGCGTTCCTGAAAATGATCGATTGGCTTCCATAGCTGCTGAATTGCAGTTTAGGTCCCTGAGTCGTCACTCAAGCCCCACGGAGGAGCGAGATGAACCAGCATATCCAAGAGGAGATTCAAGTGGGTCCACAAGAAGAAGTTGGGAACTTCGGACACTAATCAGCCAGAGTAAAGATACTGCTTCTAAACTAGGACCCATAGAAGCTATCCAGAAGTCAGTCCGATTGTTTGAAGAAAAGAGGTACCGAGAAATGAGGAGAAAGAATATCATTGGTCAAGTTTGTGATACGCCTAAGTCCTATGATAATGTTATGCACGTTGGCTTGAGGAAGGTGACCTTCAAATGGCAAAGAGGAAACAAAATTGGAGAAGGCCAGTATGGGAAGGTGTACACCTGCATCAGCGTCGACACCGGGGAGCTGATGGCCATGAAAGAGATTCGATTTCAACCTAATGACCATAAGACTATCAAGGAAACTGCAGACGAATTGAAAATATTCGAAGGCATCAAACACCCCAATCTGGTTCGGTATTTTGGTGTGGAGCTCCATAGAGAAGAAATGTACATCTTCATGGAGTACTGCGATGAGGGGACTTTAGAAGAGGTGTCAAGGCTGGGACTTCAGGAACATGTGATTAGGCTGTATTCAAAGCAGATCACCATTGCGATCAACGTCCTCCATGAGCATGGCATAGTCCACCGTGACATTAAAGGTGCCAATATCTTCCTTACCTCATCTGGATTAATCAAACTGGGAGATTTTGGATGTTCAGTAAAGCTCAAAAACAATGCCCAGACCATGCCTGGTGAAGTGAACAGCACCCTGGGGACAGCAGCATACATGGCACCTGAAGTCATCACTCGTGCCAAAGGAGAGGGCCATGGGCGTGCGGCCGACATCTGGAGTCTGGGGTGTGTTGTCATAGAGATGGTGACTGGCAAGAGGCCTTGGCATGAGTATGAGCACAACTTTCAAATTATGTATAAAGTGGGGATGGGACATAAGCCACCAATCCCTGAAAGATTAAGCCCTGAAGGAAAGGACTTCCTTTCTCACTGCCTTGAGAGTGACCCAAAGATGAGATGGACCGCCAGCCAGCTCCTCGACCATTCGTTTGTCAAGGTTTGCACAGATGAAGAATG Human MEKK 6 CDS (SEQ ID NO: 23)ATGGCGGGGCCGTGTCCCCGGTCCGGGGCGGAGCGCGCCGGCAGCTGCTGGCAGGACCCGCTGGCCGTGGCGCTGAGCCGGGGCCGGCAGCTCGCGGCGCCCCCGGGCCGGGGCTGCGCGCGGAGCCGGCCGCTCAGCGTGGTCTACGTGCTGACCCGGGAGCCGCAGCCCGGGCTCGAGCCTCGGGAGGGAACCGAGGCGGAGCCGCTGCCCCTGCGCTGCCTGCGCGAGGCTTGCGCGCAGGTCCCCCGGCCGCGGCCGCCCCCGCAGCTGCGCAGCCTGCCCTTCGGGACGCTGGAGCTAGGCGACACCGCGGCTCTGGATGCCTTCTACAACGCGGATGTGGTGGTGCTGGAGGTGAGCAGCTCGCTGGTACAGCCCTCCCTGTTCTACCACCTTGGTGTGCGTGAGAGCTTCAGCATGACCAACAATGTGCTCCTCTGCTCCCAGGCCGACCTCCCTGACCTGCAGGCCCTGCGGGAGGATGTTTTCCAGAAGAACTCGGATTGCGTTGGCAGCTACACACTGATCCCCTATGTGGTGACGGCCACTGGTCGGGTGCTGTGTGGTGATGCAGGCCTTCTGCGGGGCCTGGCTGATGGGCTGGTACAGGCTGGAGTGGGGACCGAGGCCCTGCTCACTCCCCTGGTGGGCCGGCTTGCCCGCCTGCTGGAGGCCACACCCACAGACTCTTGTGGCTATTTCCGGGAGACCATTCGGCGGGACATCCGGCAGGCGCGGGAGCGGTTCAGTGGGCCACAGCTGCGGCAGGAGCTGGCTCGCCTGCAGCGGAGACTGGACAGCGTGGAGCTGCTGAGCCCCGACATCATCATGAACTTGCTGCTCTCCTACCGCGATGTGCAGGACTACTCGGCCATCATTGAGCTGGTGGAGACGCTGCAGGCCTTGCCCACCTGTGATGTGGCCGAGCAGCATAATGTCTGCTTCCACTACACTTTTGCCCTCAACCGGAGGAACAGGCCTGGGGACCGGGCGAAGGCCCTGTCTGTGCTGCTGCCGCTGGTACAGCTTGAGGGCTCTGTGGCGCCCGATCTGTACTGCATGTGTGGCCGTATCTACAAGGACATGTTCTTCAGCTCGGGTTTCCAGGATGCTGGGCACCGGGAGCAGGCCTATCACTGGTATCGCAAGGCTTTTGACGTAGAGCCCAGCCTTCACTCAGGCATCAATGCAGCTGTGCTCCTCATTGCTGCCGGGCAGCACTTTGAGGATTCCAAAGAGCTCCGGCTAATAGGCATGAAGCTGGGCTGCCTGCTGGCCCGCAAAGGCTGCGTGGAGAAGATGCAGTATTACTGGGATGTGGGTTTCTACCTGGGAGCCCAGATCCTCGCCAATGACCCCACCCAGGTGGTGCTGGCTGCAGAGCAGCTGTATAAGCTCAATGCCCCCATATGGTACCTGGTGTCCGTGATGGAGACCTTCCTGCTCTACCAGCACTTCAGGCCCACGCCAGAGCCCCCTGGAGGGCCACCACGCCGTGCCCACTTCTGGCTCCACTTCTTGCTACAGTCCTGCCAACCATTCAAGACAGCCTGTGCCCAGGGCGACCAGTGCTTGGTGCTGGTCCTGGAGATGAACAAGGTGCTGCTGCCTGCAAAGCTCGAGGTTCGGGGTACTGACCCAGTAAGCACAGTGACCCTGAGCCTGCTGGAGCCTGAGACCCAGGACATTCCCTCCAGCTGGACCTTCCCAGTCGCCTCCATATGCGGAGTCAGCGCCTCAAAGCGCGACGAGCGCTGCTGCTTCCTCTATGCACTCCCCCCGGCTCAGGACGTCCAGCTGTGCTTCCCCAGCGTAGGGCACTGCCAGTGGTTCTGCGGCCTGATCCAGGCCTGGGTGACGAACCCGGATTCCACGGCGCCCGCGGAGGAGGCGGAGGGCGCGGGGGAGATGTTGGAGTTTGATTATGAGTACACGGAGACGGGCGAGCGGCTGGTGCTGGGCAAGGGCACGTATGGGGTGGTGTACGCGGGCCGCGATCGCCACACGAGGGTGCGCATCGCCATCAAGGAGATCCCGGAGCGGGACAGCAGGTTCTCTCAGCCCCTGCATGAAGAGATCGCTCTTCACAGACGCCTGCGCCACAAGAACATAGTGCGCTATCTGGGCTCAGCTAGCCAGGGCGGCTACCTTAAGATCTTCATGGAGGAAGTGCCTGGAGGCAGCCTGTCCTCCTTGCTGCGGTCGGTGTGGGGACCCCTGAAGGACAACGAGAGCACCATCAGTTTCTACACCCGCCAGATCCTGCAGGGACTTGGCTACTTGCACGACAACCACATCGTGCACAGGGACATAAAAGGGGACAATGTGCTGATCAACACCTTCAGTGGGCTGCTCAAGATTTCTGACTTCGGCACCTCCAAGCGGCTGGCAGGCATCACACCTTGCACTGAGACCTTCACAGGAACTCTGCAGTATATGGCCCCAGAAATCATTGACCAGGGCCCACGCGGGTATGGGAAAGCAGCTGACATCTGGTCACTGGGCTGCACTGTCATTGAGATGGCCACAGGTCGCCCCCCCTTCCACGAGCTCGGGAGCCCACAGGCTGCCATGTTTCAGGTGGGTATGTACAAGGTCCATCCGCCAATGCCCAGCTCTCTGTCGGCCGAGGCCCAAGCCTTTCTCCTCCGAACTTTTGAGCCAGACCCCCGCCTCCGAGCCAGCGCCCAGACACTGCTGGGGGACCCCTTCCTGCAGCCTGGGAAAAGGAGCCGCAGCCCCAGCTCCCCACGACATGCTCCACGGCCCTCAGATGCCCCTTCTGCCAGTCCCACTCCTTCAGCCAACTCAACCACCCAGTCTCAGACATTCCCGTGCCCTCAGGCACCCTCTCAGCACCCACCCAGCCCCCCGAAGCGCTGCCTCAGTTATGGGGGCACCAGCCAGCTCCGGGTGCCCGAGGAGCCTGCGGCCGAGGAGCCTGCGTCTCCGGAGGAGAGTTCGGGGCTGAGCCTGCTGCACCAGGAGAGCAAGCGTCGGGCCATGCTGGCCGCAGTATTGGAGCAGGAGCTGCCAGCGCTGGCGGAGAATCTGCACCAGGAGCAGAAGCAAGAGCAGGGGGCCCGTCTGGGCAGAAACCATGTGGAAGAGCTGCTGCGCTGCCTCGGGGCACACATCCACACTCCCAACCGCCGGCAGCTCGCCCAGGAGCTGCGGGCGCTGCAAGGACGGCTGAGGGCCCAGGGCCTTGGGCCTGCGCTTCTGCACAGACCGCTGTTTGCCTTCCCGGATGCGGTGAAGCAGATCCTCCGCAAGCGCCAGATCCGTCCACACTGGATGTTCGTTCTGGACTCACTGCTCAGCCGTGCTGTGCGGGCAGCCCTGGGTGTGCTAGGACCGGAGGTGGAGAAGGAGGCGGTCTCACCGAGGTCAGAGGAGCTGAGTAATGAAGGGGACTCCCAGCAGAGCCCAGGCCAGCAGAGCCCGCTTCCGGTGGAGCCCGAGCAGGGCCCCGCTCCTCTGATGGTGCAGCTGAGCCTCTTGAGGGCAGAGACTGATCGGCTGCGCGAAATCCTGGCGGGGAAGGAACGGGAGTACCAGGCCCTGGTGCAGCGGGCTCTACAGCGGCTGAATGAGGAAGCCCGGACCTATGTCCTGGCCCCAGAGCCTCCAACTGCTCTTTCAACGGACCAGGGCCTGGTGCAGTGGCTACAGGAACTGAATGTGGATTCAGGCACCATCCAAATGCTGTTGAACCATAGCTTCACCCTCCACACTCTGCTCACCTATGCCACTCGAGATGACCTCATCTACACCCGCATCAGGGGAGGGATGGTATGCCGCATCTGGAGGGCCATCTTGGCACAGCGAGCAGGATCCACACCAG TCACCTCTGGACCCTGAHuman MEKK7 CDS (SEQ ID NO: 24)ATGTCTACAGCCTCTGCCGCCTCCTCCTCCTCCTCGTCTTCGGCCGGTGAGATGATCGAAGCCCCTTCCCAGGTCCTCAACTTTGAAGAGATCGACTACAAGGAGATCGAGGTGGAAGAGGTTGTTGGAAGAGGAGCCTTTGGAGTTGTTTGCAAAGCTAAGTGGAGAGCAAAAGATGTTGCTATTAAACAAATAGAAAGTGAATCTGAGAGGAAAGCGTTTATTGTAGAGCTTCGGCAGTTATCCCGTGTGAACCATCCTAATATTGTAAAGCTTTATGGAGCCTGCTTGAATCCAGTGTGTCTTGTGATGGAATATGCTGAAGGGGGCTCTTTATATAATGTGCTGCATGGTGCTGAACCATTGCCATATTATACTGCTGCCCACGCAATGAGTTGGTGTTTACAGTGTTCCCAAGGAGTGGCTTATCTTCACAGCATGCAACCCAAAGCGCTAATTCACAGGGACCTGAAACCACCAAACTTACTGCTGGTTGCAGGGGGGACAGTTCTAAAAATTTGTGATTTTGGTACAGCCTGTGACATTCAGACACACATGACCAATAACAAGGGGAGTGCTGCTTGGATGGCACCTGAAGTTTTTGAAGGTAGTAATTACAGTGAAAAATGTGACGTCTTCAGCTGGGGTATTATTCTTTGGGAAGTGATAACGCGTCGGAAACCCTTTGATGAGATTGGTGGCCCAGCTTTCCGAATCATGTGGGCTGTTCATAATGGTACTCGACCACCACTGATAAAAAATTTACCTAAGCCCATTGAGAGCCTGATGACTCGTTGTTGGTCTAAAGATCCTTCCCAGCGCCCTTCAATGGAGGAAATTGTGAAAATAATGACTCACTTGATGCGGTACTTTCCAGGAGCAGATGAGCCATTACAGTATCCTTGTCAGTATTCAGATGAAGGACAGAGCAACTCTGCCACCAGTACAGGCTCATTCATGGACATTGCTTCTACAAATACGAGTAACAAAAGTGACACTAATATGGAGCAAGTTCCTGCCACAAATGATACTATTAAGCGCTTAGAATCAAAATTGTTGAAAAATCAGGCAAAGCAACAGAGTGAATCTGGACGTTTAAGCTTGGGAGCCTCCCGTGGGAGCAGTGTGGAGAGCTTGCCCCCAACCTCTGAGGGCAAGAGGATGAGTGCTGACATGTCTGAAATAGAAGCTAGGATCGCCGCAACCACAGGCAACGGACAGCCAAGACGTAGATCCATCCAAGACTTGACTGTAACTGGAACAGAACCTGGTCAGGTGAGCAGTAGGTCATCCAGTCCCAGTGTCAGAATGATTACTACCTCAGGACCAACCTCAGAAAAGCCAACTCGAAGTCATCCATGGACCCCTGATGATTCCACAGATACCAATGGATCAGATAACTCCATCCCAATGGCTTATCTTACACTGGATCACCAACTACAGCCTCTAGCACCGTGCCCAAACTCCAAAGAATCTATGGCAGTGTTTGAACAGCATTGTAAAATGGCACAAGAATATATGAAAGTTCAAACAGAAATTGCATTGTTATTACAGAGAAAGCAAGAACTAGTTGCAGAACTGGACCAGGATGAAAAGGACCAGCAAAATACATCTCGCCTGGTACAGGAACATAAAAAGCTTTTAGATGAAAACAAAAGCCTTTCTACTTACTACCAGCAATGCAAAAAACAACTAGAGGTCATCAGAAGTCAGCAGCAGAAACGACAAGGCACTTCATGA Human MK2 CDS (SEQ ID NO: 25)ATGCTGTCCAACTCCCAGGGCCAGAGCCCGCCGGTGCCGTTCCCCGCCCCGGCCCCGCCGCCGCAGCCCCCCACCCCTGCCCTGCCGCACCCCCCGGCGCAGCCGCCGCCGCCGCCCCCGCAGCAGTTCCCGCAGTTCCACGTCAAGTCCGGCCTGCAGATCAAGAAGAACGCCATCATCGATGACTACAAGGTCACCAGCCAGGTCCTGGGGCTGGGCATCAACGGCAAAGTTTTGCAGATCTTCAACAAGAGGACCCAGGAGAAATTCGCCCTCAAAATGCTTCAGGACTGCCCCAAGGCCCGCAGGGAGGTGGAGCTGCACTGGCGGGCCTCCCAGTGCCCGCACATCGTACGGATCGTGGATGTGTACGAGAATCTGTACGCAGGGAGGAAGTGCCTGCTGATTGTCATGGAATGTTTGGACGGTGGAGAACTCTTTAGCCGAATCCAGGATCGAGGAGACCAGGCATTCACAGAAAGAGAAGCATCCGAAATCATGAAGAGCATCGGTGAGGCCATCCAGTATCTGCATTCAATCAACATTGCCCATCGGGATGTCAAGCCTGAGAATCTCTTATACACCTCCAAAAGGCCCAACGCCATCCTGAAACTCACTGACTTTGGCTTTGCCAAGGAAACCACCAGCCACAACTCTTTGACCACTCCTTGTTATACACCGTACTATGTGGCTCCAGAAGTGCTGGGTCCAGAGAAGTATGACAAGTCCTGTGACATGTGGTCCCTGGGTGTCATCATGTACATCCTGCTGTGTGGGTATCCCCCCTTCTACTCCAACCACGGCCTTGCCATCTCTCCGGGCATGAAGACTCGCATCCGAATGGGCCAGTATGAATTTCCCAACCCAGAATGGTCAGAAGTATCAGAGGAAGTGAAGATGCTCATTCGGAATCTGCTGAAAACAGAGCCCACCCAGAGAATGACCATCACCGAGTTTATGAACCACCCTTGGATCATGCAATCAACAAAGGTCCCTCAAACCCCACTGCACACCAGCCGGGTCCTGAAGGAGGACAAGGAGCGGTGGGAGGATGTCAAGGGGTGTCTTCATGACAAGAACAGCGACCAGGCCACTTGGCT GACCAGGTTGTGAHuman MyD88 CDS (SEQ ID NO: 26)ATGCGACCCGACCGCGCTGAGGCTCCAGGACCGCCCGCCATGGCTGCAGGAGGTCCCGGCGCGGGGTCTGCGGCCCCGGTCTCCTCCACATCCTCCCTTCCCCTGGCTGCTCTCAACATGCGAGTGCGGCGCCGCCTGTCTCTGTTCTTGAACGTGCGGACACAGGTGGCGGCCGACTGGACCGCGCTGGCGGAGGAGATGGACTTTGAGTACTTGGAGATCCGGCAACTGGAGACACAAGCGGACCCCACTGGCAGGCTGCTGGACGCCTGGCAGGGACGCCCTGGCGCCTCTGTAGGCCGACTGCTCGAGCTGCTTACCAAGCTGGGCCGCGACGACGTGCTGCTGGAGCTGGGACCCAGCATTGAGGAGGATTGCCAAAAGTATATCTTGAAGCAGCAGCAGGAGGAGGCTGAGAAGCCTTTACAGGTGGCCGCTGTAGACAGCAGTGTCCCACGGACAGCAGAGCTGGCGGGCATCACCACACTTGATGACCCCCTGGGGCATATGCCTGAGCGTTTCGATGCCTTCATCTGCTATTGCCCCAGCGACATCCAGTTTGTGCAGGAGATGATCCGGCAACTGGAACAGACAAACTATCGACTGAAGTTGTGTGTGTCTGACCGCGATGTCCTGCCTGGCACCTGTGTCTGGTCTATTGCTAGTGAGCTCATCGAAAAGAGGTTGGCTAGAAGGCCACGGGGTGGGTGCCGCCGGATGGTGGTGGTTGTCTCTGATGATTACCTGCAGAGCAAGGAATGTGACTTCCAGACCAAATTTGCACTCAGCCTCTCTCCAGGTGCCCATCAGAAGCGACTGATCCCCATCAAGTACAAGGCAATGAAGAAAGAGTTCCCCAGCATCCTGAGGTTCATCACTGTCTGCGACTACACCAACCCCTGCACCAAATCTTGGTTCTGGACTCGCCTTGCCAAGGCCTTGTCCCTGCC CTGAHuman NF-κB CDS (SEQ ID NO: 27)ATGGCAGAAGATGATCCATATTTGGGAAGGCCTGAACAAATGTTTCATTTGGATCCTTCTTTGACTCATACAATATTTAATCCAGAAGTATTTCAACCACAGATGGCACTGCCAACAGATGGCCCATACCTTCAAATATTAGAGCAACCTAAACAGAGAGGATTTCGTTTCCGTTATGTATGTGAAGGCCCATCCCATGGTGGACTACCTGGTGCCTCTAGTGAAAAGAACAAGAAGTCTTACCCTCAGGTCAAAATCTGCAACTATGTGGGACCAGCAAAGGTTATTGTTCAGTTGGTCACAAATGGAAAAAATATCCACCTGCATGCCCACAGCCTGGTGGGAAAACACTGTGAGGATGGGATCTGCACTGTAACTGCTGGACCCAAGGACATGGTGGTCGGCTTCGCAAACCTGGGTATACTTCATGTGACAAAGAAAAAAGTATTTGAAACACTGGAAGCACGAATGACAGAGGCGTGTATAAGGGGCTATAATCCTGGACTCTTGGTGCACCCTGACCTTGCCTATTTGCAAGCAGAAGGTGGAGGGGACCGGCAGCTGGGAGATCGGGAAAAAGAGCTAATCCGCCAAGCAGCTCTGCAGCAGACCAAGGAGATGGACCTCAGCGTGGTGCGGCTCATGTTTACAGCTTTTCTTCCGGATAGCACTGGCAGCTTCACAAGGCGCCTGGAACCCGTGGTATCAGACGCCATCTATGACAGTAAAGCCCCCAATGCATCCAACTTGAAAATTGTAAGAATGGACAGGACAGCTGGATGTGTGACTGGAGGGGAGGAAATTTATCTTCTTTGTGACAAAGTTCAGAAAGATGACATCCAGATTCGATTTTATGAAGAGGAAGAAAATGGTGGAGTCTGGGAAGGATTTGGAGATTTTTCCCCCACAGATGTTCATAGACAATTTGCCATTGTCTTCAAAACTCCAAAGTATAAAGATATTAATATTACAAAACCAGCCTCTGTGTTTGTCCAGCTTCGGAGGAAATCTGACTTGGAAACTAGTGAACCAAAACCTTTCCTCTACTATCCTGAAATCAAAGATAAAGAAGAAGTGCAGAGGAAACGTCAGAAGCTCATGCCCAATTTTTCGGATAGTTTCGGCGGTGGTAGTGGTGCTGGAGCTGGAGGCGGAGGCATGTTTGGTAGTGGCGGTGGAGGAGGGGGCACTGGAAGTACAGGTCCAGGGTATAGCTTCCCACACTATGGATTTCCTACTTATGGTGGGATTACTTTCCATCCTGGAACTACTAAATCTAATGCTGGGATGAAGCATGGAACCATGGACACTGAATCTAAAAAGGACCCTGAAGGTTGTGACAAAAGTGATGACAAAAACACTGTAAACCTCTTTGGGAAAGTTATTGAAACCACAGAGCAAGATCAGGAGCCCAGCGAGGCCACCGTTGGGAATGGTGAGGTCACTCTAACGTATGCAACAGGAACAAAAGAAGAGAGTGCTGGAGTTCAGGATAACCTCTTTCTAGAGAAGGCTATGCAGCTTGCAAAGAGGCATGCCAATGCCCTTTTCGACTACGCGGTGACAGGAGACGTGAAGATGCTGCTGGCCGTCCAGCGCCATCTCACTGCTGTGCAGGATGAGAATGGGGACAGTGTCTTACACTTAGCAATCATCCACCTTCATTCTCAACTTGTGAGGGATCTACTAGAAGTCACATCTGGTTTGATTTCTGATGACATTATCAACATGAGAAATGATCTGTACCAGACGCCCTTGCACTTGGCAGTGATCACTAAGCAGGAAGATGTGGTGGAGGATTTGCTGAGGGCTGGGGCCGACCTGAGCCTTCTGGACCGCTTGGGTAACTCTGTTTTGCACCTAGCTGCCAAAGAAGGACATGATAAAGTTCTCAGTATCTTACTCAAGCACAAAAAGGCAGCACTACTTCTTGACCACCCCAACGGGGACGGTCTGAATGCCATTCATCTAGCCATGATGAGCAATAGCCTGCCATGTTTGCTGCTGCTGGTGGCCGCTGGGGCTGACGTCAATGCTCAGGAGCAGAAGTCCGGGCGCACAGCACTGCACCTGGCTGTGGAGCACGACAACATCTCATTGGCAGGCTGCCTGCTCCTGGAGGGTGATGCCCATGTGGACAGTACTACCTACGATGGAACCACACCCCTGCATATAGCAGCTGGGAGAGGGTCCACCAGGCTGGCAGCTCTTCTCAAAGCAGCAGGAGCAGATCCCCTGGTGGAGAACTTTGAGCCTCTCTATGACCTGGATGACTCTTGGGAAAATGCAGGAGAGGATGAAGGAGTTGTGCCTGGAACCACGCCTCTAGATATGGCCACCAGCTGGCAGGTATTTGACATATTAAATGGGAAACCATATGAGCCAGAGTTTACATCTGATGATTTACTAGCACAAGGAGACATGAAACAGCTGGCTGAAGATGTGAAGCTGCAGCTGTATAAGTTACTAGAAATTCCTGATCCAGACAAAAACTGGGCTACTCTGGCGCAGAAATTAGGTCTGGGGATACTTAATAATGCCTTCCGGCTGAGTCCTGCTCCTTCCAAAACACTTATGGACAACTATGAGGTCTCTGGGGGTACAGTCAGAGAGCTGGTGGAGGCCCTGAGACAAATGGGCTACACCGAAGCAATTGAAGTGATCCAGGCAGCCTCCAGCCCAGTGAAGACCACCTCTCAGGCCCACTCGCTGCCTCTCTCGCCTGCCTCCACAAGGCAGCAAATAGACGAGCTCCGAGACAGTGACAGTGTCTGCGACAGCGGCGTGGAGACATCCTTCCGCAAACTCAGCTTTACCGAGTCTCTGACCAGTGGTGCCTCACTGCTAACTCTCAACAAAATGCCCCATGATTATGGGCAGGAAGGACCTCTAGAAGGCAA AATTTAGHuman NIK CDS (SEQ ID NO: 28)ATGGCAGTGATGGAAATGGCCTGCCCAGGTGCCCCTGGCTCAGCAGTGGGGCAGCAGAAGGAACTCCCCAAAGCCAAGGAGAAGACGCCGCCACTGGGGAAGAAACAGAGCTCCGTCTACAAGCTTGAGGCCGTGGAGAAGAGCCCTGTGTTCTGCGGAAAGTGGGAGATCCTGAATGACGTGATTACCAAGGGCACAGCCAAGGAAGGCTCCGAGGCAGGGCCAGCTGCCATCTCTATCATCGCCCAGGCTGAGTGTGAGAATAGCCAAGAGTTCAGCCCCACCTTTTCAGAACGCATTTTCATCGCTGGGTCCAAACAGTACAGCCAGTCCGAGAGTCTTGATCAGATCCCCAACAATGTGGCCCATGCTACAGAGGGCAAAATGGCCCGTGTGTGTTGGAAGGGAAAGCGTCGCAGCAAAGCCCGGAAGAAACGGAAGAAGAAGAGCTCAAAGTCCCTGGCTCATGCAGGAGTGGCCTTGGCCAAACCCCTCCCCAGGACCCCTGAGCAGGAGAGCTGCACCATCCCAGTGCAGGAGGATGAGTCTCCACTCGGCGCCCCATATGTTAGAAACACCCCGCAGTTCACCAAGCCTCTGAAGGAACCAGGCCTTGGGCAACTCTGTTTTAAGCAGCTTGGCGAGGGCCTACGGCCGGCTCTGCCTCGATCAGAACTCCACAAACTGATCAGCCCCTTGCAATGTCTGAACCACGTGTGGAAACTGCACCACCCCCAGGACGGAGGCCCCCTGCCCCTGCCCACGCACCCCTTCCCCTATAGCAGACTGCCTCATCCCTTCCCATTCCACCCTCTCCAGCCCTGGAAACCTCACCCTCTGGAGTCCTTCCTGGGCAAACTGGCCTGTGTAGACAGCCAGAAACCCTTGCCTGACCCACACCTGAGCAAACTGGCCTGTGTAGACAGTCCAAAGCCCCTGCCTGGCCCACACCTGGAGCCCAGCTGCCTGTCTCGTGGTGCCCATGAGAAGTTTTCTGTGGAGGAATACCTAGTGCATGCTCTGCAAGGCAGCGTGAGCTCAGGCCAGGCCCACAGCCTGACCAGCCTGGCCAAGACCTGGGCAGCAAGGGGCTCCAGATCCCGGGAGCCCAGCCCCAAAACTGAGGACAACGAGGGTGTCCTGCTCACTGAGAAACTCAAGCCAGTGGATTATGAGTACCGAGAAGAAGTCCACTGGGCCACGCACCAGCTCCGCCTGGGCAGAGGCTCCTTCGGAGAGGTGCACAGGATGGAGGACAAGCAGACTGGCTTCCAGTGCGCTGTCAAAAAGGTGCGGCTGGAAGTATTTCGGGCAGAGGAGCTGATGGCATGTGCAGGATTGACCTCACCCAGAATTGTCCCTTTGTATGGAGCTGTGAGAGAAGGGCCTTGGGTCAACATCTTCATGGAGCTGCTGGAAGGTGGCTCCCTGGGCCAGCTGGTCAAGGAGCAGGGCTGTCTCCCAGAGGACCGGGCCCTGTACTACCTGGGCCAGGCCCTGGAGGGTCTGGAATACCTCCACTCACGAAGGATTCTGCATGGGGACGTCAAAGCTGACAACGTGCTCCTGTCCAGCGATGGGAGCCACGCAGCCCTCTGTGACTTTGGCCATGCTGTGTGTCTTCAACCTGATGGCCTGGGAAAGTCCTTGCTCACAGGGGACTACATCCCTGGCACAGAGACCCACATGGCTCCGGAGGTGGTGCTGGGCAGGAGCTGCGACGCCAAGGTGGATGTCTGGAGCAGCTGCTGTATGATGCTGCACATGCTCAACGGCTGCCACCCCTGGACTCAGTTCTTCCGAGGGCCGCTCTGCCTCAAGATTGCCAGCGAGCCTCCGCCTGTGAGGGAGATCCCACCCTCCTGCGCCCCTCTCACAGCCCAGGCCATCCAAGAGGGGCTGAGGAAAGAGCCCATCCACCGCGTGTCTGCAGCGGAGCTGGGAGGGAAGGTGAACCGGGCACTACAGCAAGTGGGAGGTCTGAAGAGCCCTTGGAGGGGAGAATATAAAGAACCAAGACATCCACCGCCAAATCAAGCCAATTACCACCAGACCCTCCATGCCCAGCCGAGAGAGCTTTCGCCAAGGGCCCCAGGGCCCCGGCCAGCTGAGGAGACAACAGGCAGAGCCCCTAAGCTCCAGCCTCCTCTCCCACCAGAGCCCCCAGAGCCAAACAAGTCTCCTCCCTTGACTTTGAGCAAGGAGGAGTCTGGGATGTGGGAACCCTTACCTCTGTCCTCCCTGGAGCCAGCCCCTGCCAGAAACCCCAGCTCACCAGAGCGGAAAGCAACCGTCCCGGAGCAGGAACTGCAGCAGCTGGAAATAGAATTATTCCTCAACAGCCTGTCCCAGCCATTTTCTCTGGAGGAGCAGGAGCAAATTCTCTCGTGCCTCAGCATCGACAGCCTCTCCCTGTCGGATGACAGTGAGAAGAACCCATCAAAGGCCTCTCAAAGCTCGCGGGACACCCTGAGCTCAGGCGTACACTCCTGGAGCAGCCAGGCCGAGGCTCGAAGCTCCAGCTGGAACATGGTGCTGGCCCGGGGGCGGCCCACCGACACCCCAAGCTATTTCAATGGTGTGAAAGTCCAAATACAGTCTCTTAATGGTGAACACCTGCACATCCGGGAGTTCCACCGGGTCAAAGTGGGAGACATCGCCACTGGCATCAGCAGCCAGATCCCAGCTGCAGCCTTCAGCTTGGTCACCAAAGACGGGCAGCCTGTTCGCTACGACATGGAGGTGCCAGACTCGGGCATCGACCTGCAGTGCACACTGGCCCCTGATGGCAGCTTCGCCTGGAGCTGGAGGGTCAAGCATGGCCAGCTGGAGAACAGGCCCTAAHuman p38 CDS (SEQ ID NO: 29)ATGTCTCAGGAGAGGCCCACGTTCTACCGGCAGGAGCTGAACAAGACAATCTGGGAGGTGCCCGAGCGTTACCAGAACCTGTCTCCAGTGGGCTCTGGCGCCTATGGCTCTGTGTGTGCTGCTTTTGACACAAAAACGGGGTTACGTGTGGCAGTGAAGAAGCTCTCCAGACCATTTCAGTCCATCATTCATGCGAAAAGAACCTACAGAGAACTGCGGTTACTTAAACATATGAAACATGAAAATGTGATTGGTCTGTTGGACGTTTTTACACCTGCAAGGTCTCTGGAGGAATTCAATGATGTGTATCTGGTGACCCATCTCATGGGGGCAGATCTGAACAACATTGTGAAATGTCAGAAGCTTACAGATGACCATGTTCAGTTCCTTATCTACCAAATTCTCCGAGGTCTAAAGTATATACATTCAGCTGACATAATTCACAGGGACCTAAAACCTAGTAATCTAGCTGTGAATGAAGACTGTGAGCTGAAGATTCTGGATTTTGGACTGGCTCGGCACACAGATGATGAAATGACAGGCTACGTGGCCACTAGGTGGTACAGGGCTCCTGAGATCATGCTGAACTGGATGCATTACAACCAGACAGTTGATATTTGGTCAGTGGGATGCATAATGGCCGAGCTGTTGACTGGAAGAACATTGTTTCCTGGTACAGACCATATTAACCAGCTTCAGCAGATTATGCGTCTGACAGGAACACCCCCCGCTTATCTCATTAACAGGATGCCAAGCCATGAGGCAAGAAACTATATTCAGTCTTTGACTCAGATGCCGAAGATGAACTTTGCGAATGTATTTATTGGTGCCAATCCCCTGGCTGTCGACTTGCTGGAGAAGATGCTTGTATTGGACTCAGATAAGAGAATTACAGCGGCCCAAGCCCTTGCACATGCCTACTTTGCTCAGTACCACGATCCTGATGATGAACCAGTGGCCGATCCTTATGATCAGTCCTTTGAAAGCAGGGACCTCCTTATAGATGAGTGGAAAAGCCTGACCTATGATGAAGTCATCAGCTTTGTGCCACCACCCCTTGACCAAGAAGAGATGGAGTCCTGA Human PKR CDS (SEQ ID NO: 30)ATGGCTGGTGATCTTTCAGCAGGTTTCTTCATGGAGGAACTTAATACATACCGTCAGAAGCAGGGAGTAGTACTTAAATATCAAGAACTGCCTAATTCAGGACCTCCACATGATAGGAGGTTTACATTTCAAGTTATAATAGATGGAAGAGAATTTCCAGAAGGTGAAGGTAGATCAAAGAAGGAAGCAAAAAATGCCGCAGCCAAATTAGCTGTTGAGATACTTAATAAGGAAAAGAAGGCAGTTAGTCCTTTATTATTGACAACAACGAATTCTTCAGAAGGATTATCCATGGGGAATTACATAGGCCTTATCAATAGAATTGCCCAGAAGAAAAGACTAACTGTAAATTATGAACAGTGTGCATCGGGGGTGCATGGGCCAGAAGGATTTCATTATAAATGCAAAATGGGACAGAAAGAATATAGTATTGGTACAGGTTCTACTAAACAGGAAGCAAAACAATTGGCCGCTAAACTTGCATATCTTCAGATATTATCAGAAGAAACCTCAGTGAAATCTGACTACCTGTCCTCTGGTTCTTTTGCTACTACGTGTGAGTCCCAAAGCAACTCTTTAGTGACCAGCACACTCGCTTCTGAATCATCATCTGAAGGTGACTTCTCAGCAGATACATCAGAGATAAATTCTAACAGTGACAGTTTAAACAGTTCTTCGTTGCTTATGAATGGTCTCAGAAATAATCAAAGGAAGGCAAAAAGATCTTTGGCACCCAGATTTGACCTTCCTGACATGAAAGAAACAAAGTATACTGTGGACAAGAGGTTTGGCATGGATTTTAAAGAAATAGAATTAATTGGCTCAGGTGGATTTGGCCAAGTTTTCAAAGCAAAACACAGAATTGACGGAAAGACTTACGTTATTAAACGTGTTAAATATAATAACGAGAAGGCGGAGCGTGAAGTAAAAGCATTGGCAAAACTTGATCATGTAAATATTGTTCACTACAATGGCTGTTGGGATGGATTTGATTATGATCCTGAGACCAGTGATGATTCTCTTGAGAGCAGTGATTATGATCCTGAGAACAGCAAAAATAGTTCAAGGTCAAAGACTAAGTGCCTTTTCATCCAAATGGAATTCTGTGATAAAGGGACCTTGGAACAATGGATTGAAAAAAGAAGAGGCGAGAAACTAGACAAAGTTTTGGCTTTGGAACTCTTTGAACAAATAACAAAAGGGGTGGATTATATACATTCAAAAAAATTAATTCATAGAGATCTTAAGCCAAGTAATATATTCTTAGTAGATACAAAACAAGTAAAGATTGGAGACTTTGGACTTGTAACATCTCTGAAAAATGATGGAAAGCGAACAAGGAGTAAGGGAACTTTGCGATACATGAGCCCAGAACAGATTTCTTCGCAAGACTATGGAAAGGAAGTGGACCTCTACGCTTTGGGGCTAATTCTTGCTGAACTTCTTCATGTATGTGACACTGCTTTTGAAACATCAAAGTTTTTCACAGACCTACGGGATGGCATCATCTCAGATATATTTGATAAAAAAGAAAAAACTCTTCTACAGAAATTACTCTCAAAGAAACCTGAGGATCGACCTAACACATCTGAAATACTAAGGACCTTGACTGTGTGGAAGAAAAGCCCAGAGAAAAATGAACGACACACA TGTTAGHuman Rac CDS (SEQ ID NO: 31)ATGAGCGACGTGGCTATTGTGAAGGAGGGTTGGCTGCACAAACGAGGGGAGTACATCAAGACCTGGCGGCCACGCTACTTCCTCCTCAAGAATGATGGCACCTTCATTGGCTACAAGGAGCGGCCGCAGGATGTGGACCAACGTGAGGCTCCCCTCAACAACTTCTCTGTGGCGCAGTGCCAGCTGATGAAGACGGAGCGGCCCCGGCCCAACACCTTCATCATCCGCTGCCTGCAGTGGACCACTGTCATCGAACGCACCTTCCATGTGGAGACTCCTGAGGAGCGGGAGGAGTGGACAACCGCCATCCAGACTGTGGCTGACGGCCTCAAGAAGCAGGAGGAGGAGGAGATGGACTTCCGGTCGGGCTCACCCAGTGACAACTCAGGGGCTGAAGAGATGGAGGTGTCCCTGGCCAAGCCCAAGCACCGCGTGACCATGAACGAGTTTGAGTACCTGAAGCTGCTGGGCAAGGGCACTTTCGGCAAGGTGATCCTGGTGAAGGAGAAGGCCACAGGCCGCTACTACGCCATGAAGATCCTCAAGAAGGAAGTCATCGTGGCCAAGGACGAGGTGGCCCACACACTCACCGAGAACCGCGTCCTGCAGAACTCCAGGCACCCCTTCCTCACAGCCCTGAAGTACTCTTTCCAGACCCACGACCGCCTCTGCTTTGTCATGGAGTACGCCAACGGGGGCGAGCTGTTCTTCCACCTGTCCCGGGAGCGTGTGTTCTCCGAGGACCGGGCCCGCTTCTATGGCGCTGAGATTGTGTCAGCCCTGGACTACCTGCACTCGGAGAAGAACGTGGTGTACCGGGACCTCAAGCTGGAGAACCTCATGCTGGACAAGGACGGGCACATTAAGATCACAGACTTCGGGCTGTGCAAGGAGGGGATCAAGGACGGTGCCACCATGAAGACCTTTTGCGGCACACCTGAGTACCTGGCCCCCGAGGTGCTGGAGGACAATGACTACGGCCGTGCAGTGGACTGGTGGGGGCTGGGCGTGGTCATGTACGAGATGATGTGCGGTCGCCTGCCCTTCTACAACCAGGACCATGAGAAGCTTTTTGAGCTCATCCTCATGGAGGAGATCCGCTTCCCGCGCACGCTTGGTCCCGAGGCCAAGTCCTTGCTTTCAGGGCTGCTCAAGAAGGACCCCAAGCAGAGGCTTGGCGGGGGCTCCGAGGACGCCAAGGAGATCATGCAGCATCGCTTCTTTGCCGGTATCGTGTGGCAGCACGTGTACGAGAAGAAGCTCAGCCCACCCTTCAAGCCCCAGGTCACGTCGGAGACTGACACCAGGTATTTTGATGAGGAGTTCACGGCCCAGATGATCACCATCACACCACCTGACCAAGATGACAGCATGGAGTGTGTGGACAGCGAGCGCAGGCCCCACTTCCCCCAGTTCTCCTACTCGGCCAGCGGCACGGCCTGAHuman Raf CDS (SEQ ID NO: 32)ATGGCTAGCAAACGAAAATCTACAACTCCATGCATGGTTCGGACATCACAAGTAGTAGAACAAGATGTGCCCGAGGAAGTAGACAGGGCCAAAGAGAAAGGAATCGGCACACCACAGCCTGACGTGGCCAAGGACAGTTGGGCAGCAGAACTTGAAAACTCTTCCAAAGAAAACGAAGTGATAGAGGTGAAATCTATGGGGGAAAGCCAGTCCAAAAAACTCCAAGGTGGTTATGAGTGCAAATACTGCCCCTACTCCACGCAAAACCTGAACGAGTTCACGGAGCATGTCGACATGCAGCATCCCAACGTGATTCTCAACCCCCTCTACGTGTGTGCAGAATGTAACTTCACAACCAAAAAGTACGACTCCCTATCCGACCACAACTCCAAGTTCCATCCCGGGGAGGCCAACTTCAAGCTGAAGTTAATTAAACGCAATAATCAAACTGTCTTGGAACAGTCCATCGAAACCACCAACCATGTCGTGTCCATCACCACCAGTGGCCCTGGAACTGGTGACAGTGATTCTGGGATCTCGGTGAGTAAAACCCCCATCATGAAGCCTGGAAAACCAAAAGCGGATGCCAAGAAGGTGCCCAAGAAGCCCGAGGAGATCACCCCCGAGAACCACGTGGAAGGGACCGCCCGCCTGGTGACAGACACAGCTGAGATCCTCTCGAGACTCGGCGGGGTGGAGCTCCTCCAAGACACATTAGGACACGTCATGCCTTCTGTACAGCTGCCACCAAATATCAACCTTGTGCCCAAGGTCCCTGTCCCACTAAATACTACCAAATACAACTCTGCCCTGGATACAAATGCCACGATGATCAACTCTTTCAACAAGTTTCCTTACCCGACCCAGGCTGAGTTGTCCTGGCTGACAGCTGCCTCCAAACACCCAGAGGAGCACATCAGAATCTGGTTTGCCACCCAGCGCTTAAAGCATGGCATCAGCTGGTCCCCAGAAGAGGTGGAGGAGGCCCGGAAGAAGATGTTCAACGGCACCATCCAGTCAGTACCCCCGACCATCACTGTGCTGCCCGCCCAGTTGGCCCCCACAAAGGTGACGCAGCCCATCCTCCAGACGGCTCTACCGTGCCAGATCCTCGGCCAGACTAGCCTGGTGCTGACTCAGGTGACCAGCGGGTCAACAACCGTCTCTTGCTCCCCCATCACACTTGCCGTGGCAGGAGTCACCAACCATGGCCAGAAGAGACCCTTGGTGACTCCCCAAGCTGCCCCCGAACCCAAGCGTCCACACATCGCTCAGGTGCCAGAGCCCCCACCCAAGGTGGCCAACCCCCCGCTCACACCAGCCAGTGACCGCAAGAAGACAAAGGAGCAGATAGCACATCTCAAGGCCAGCTTTCTCCAGAGCCAGTTCCCTGACGATGCCGAGGTTTACCGGCTCATCGAGGTGACTGGCCTTGCCAGGAGCGAGATCAAGAAGTGGTTCAGTGACCACCGATATCGGTGTCAAAGGGGCATCGTCCACATCACCAGCGAATCCCTTGCCAAAGACCAGTTGGCCATCGCGGCCTCCCGACACGGTCGCACGTATCATGCGTACCCAGACTTTGCCCCCCAGAAGTTCAAAGAGAAAACACAGGGTCAGGTTAAAATCTTGGAAGACAGCTTTTTGAAAAGTTCTTTTCCTACCCAAGCAGAACTGGATCGGCTAAGGGTGGAGACCAAGCTGAGCAGGAGAGAGATCGACTCCTGGTTCTCGGAGAGGCGGAAGCTTCGAGACAGCATGGAACAAGCTGTCTTGGATTCCATGGGGTCTGGCAAAAAAGGCCAAGATGTGGGAGCCCCCAATGGTGCTCTGTCTCGACTCGACCAGCTCTCCGGTGCCCAGTTAACAAGTTCTCTGCCCAGCCCTTCGCCAGCAATTGCAAAAAGTCAAGAACAGGTTCATCTCCTGAGGAGCACGTTTGCAAGAACCCAGTGGCCTACTCCCCAGGAGTACGACCAGTTAGCGGCCAAGACTGGCCTGGTCCGAACTGAGATTGTGCGTTGGTTCAAGGAGAACAGATGCTTGCTGAAAACGGGAACCGTGAAGTGGATGGAGCAGTACCAGCACCAGCCCATGGCAGATGATCACGGCTACGATGCCGTAGCAAGGAAAGCAACAAAACCCATGGCCGAGAGCCCAAAGAACGGGGGTGATGTGGTTCCACAATATTACAAGGACCCCAAAAAGCTCTGCGAAGAGGACTTGGAGAAGTTGGTGACCAGGGTAAAAGTAGGCAGCGAGCCAGCAAAAGACTGTTTGCCAGCAAAGCCCTCAGAGGCCACCTCAGACCGGTCAGAGGGCAGCAGCCGGGACGGCCAGGGTAGCGACGAGAACGAGGAGTCGAGCGTTGTGGATTACGTGGAGGTGACGGTCGGGGAGGAGGATGCGATCTCAGATAGATCAGATAGCTGGAGTCAGGCTGCGGCAGAAGGTGTGTCGGAACTGGCTGAATCAGACTCCGACTGCGTCCCTGCAGAGG CTGGCCAGGCCTAGHuman K-Ras CDS (SEQ ID NO: 33)ATGACTGAATATAAACTTGTGGTAGTTGGAGCTGGTGGCGTAGGCAAGAGTGCCTTGACGATACAGCTAATTCAGAATCATTTTGTGGACGAATATGATCCAACAATAGAGGATTCCTACAGGAAGCAAGTAGTAATTGATGGAGAAACCTGTCTCTTGGATATTCTCGACACAGCAGGTCAAGAGGAGTACAGTGCAATGAGGGACCAGTACATGAGGACTGGGGAGGGCTTTCTTTGTGTATTTGCCATAAATAATACTAAATCATTTGAAGATATTCACCATTATAGAGAACAAATTAAAAGAGTTAAGGACTCTGAAGATGTACCTATGGTCCTAGTAGGAAATAAATGTGATTTGCCTTCTAGAACAGTAGACACAAAACAGGCTCAGGACTTAGCAAGAAGTTATGGAATTCCTTTTATTGAAACATCAGCAAAGACAAGACAGGGTGTTGATGATGCCTTCTATACATTAGTTCGAGAAATTCGAAAACATAAAGAAAAGATGAGCAAAGATGGTAAAAAGAAGAAAAAGAAGTCAAAGACAA AGTGTGTAATTATGTAAHuman N-Ras CDS (SEQ ID NO: 34)ATGACTGAGTACAAACTGGTGGTGGTTGGAGCAGGTGGTGTTGGGAAAAGCGCACTGACAATCCAGCTAATCCAGAACCACTTTGTAGATGAATATGATCCCACCATAGAGGATTCTTACAGAAAACAAGTGGTTATAGATGGTGAAACCTGTTTGTTGGACATACTGGATACAGCTGGACAAGAAGAGTACAGTGCCATGAGAGACCAATACATGAGGACAGGCGAAGGCTTCCTCTGTGTATTTGCCATCAATAATAGCAAGTCATTTGCGGATATTAACCTCTACAGGGAGCAGATTAAGCGAGTAAAAGACTCGGATGATGTACCTATGGTGCTAGTGGGAAACAAGTGTGATTTGCCAACAAGGACAGTTGATACAAAACAAGCCCACGAACTGGCCAAGAGTTACGGGATTCCATTCATTGAAACCTCAGCCAAGACCAGACAGGGTGTTGAAGATGCTTTTTACACACTGGTAAGAGAAATACGCCAGTACCGAATGAAAAAACTCAACAGCAGTGATGATGGGACTCAGGGTTGTATGGGAT TGCCATGTGTGGTGATGTAAHuman RIP CDS (SEQ ID NO: 35)ATGCAACCAGACATGTCCTTGAATGTCATTAAGATGAAATCCAGTGACTTCCTGGAGAGTGCAGAACTGGACAGCGGAGGCTTTGGGAAGGTGTCTCTGTGTTTCCACAGAACCCAGGGACTCATGATCATGAAAACAGTGTACAAGGGGCCCAACTGCATTGAGCACAACGAGGCCCTCTTGGAGGAGGCGAAGATGATGAACAGACTGAGACACAGCCGGGTGGTGAAGCTCCTGGGCGTCATCATAGAGGAAGGGAAGTACTCCCTGGTGATGGAGTACATGGAGAAGGGCAACCTGATGCACGTGCTGAAAGCCGAGATGAGTACTCCGCTTTCTGTAAAAGGAAGGATAATTTTGGAAATCATTGAAGGAATGTGCTACTTACATGGAAAAGGCGTGATACACAAGGACCTGAAGCCTGAAAATATCCTTGTTGATAATGACTTCCACATTAAGATCGCAGACCTCGGCCTTGCCTCCTTTAAGATGTGGAGCAAACTGAATAATGAAGAGCACAATGAGCTGAGGGAAGTGGACGGCACCGCTAAGAAGAATGGCGGCACCCTCTACTACATGGCGCCCGAGCACCTGAATGACGTCAACGCAAAGCCCACAGAGAAGTCGGATGTGTACAGCTTTGCTGTAGTACTCTGGGCGATATTTGCAAATAAGGAGCCATATGAAAATGCTATCTGTGAGCAGCAGTTGATAATGTGCATAAAATCTGGGAACAGGCCAGATGTGGATGACATCACTGAGTACTGCCCAAGAGAAATTATCAGTCTCATGAAGCTCTGCTGGGAAGCGAATCCGGAAGCTCGGCCGACATTTCCTGGCATTGAAGAAAAATTTAGGCCTTTTTATTTAAGTCAATTAGAAGAAAGTGTAGAAGAGGACGTGAAGAGTTTAAAGAAAGAGTATTCAAACGAAAATGCAGTTGTGAAGAGAATGCAGTCTCTTCAACTTGATTGTGTGGCAGTACCTTCAAGCCGGTCAAATTCAGCCACAGAACAGCCTGGTTCACTGCACAGTTCCCAGGGACTTGGGATGGGTCCTGTGGAGGAGTCCTGGTTTGCTCCTTCCCTGGAGCACCCACAAGAAGAGAATGAGCCCAGCCTGCAGAGTAAACTCCAAGACGAAGCCAACTACCATCTTTATGGCAGCCGCATGGACAGGCAGACGAAACAGCAGCCCAGACAGAATGTGGCTTACAACAGAGAGGAGGAAAGGAGACGCAGGGTCTCCCATGACCCTTTTGCACAGCAAAGACCTTACGAGAATTTTCAGAATACAGAGGGAAAAGGCACTGCTTATTCCAGTGCAGCCAGTCATGGTAATGCAGTGCACCAGCCCTCAGGGCTCACCAGCCAACCTCAAGTACTGTATCAGAACAATGGATTATATAGCTCACATGGCTTTGGAACAAGACCACTGGATCCAGGAACAGCAGGTCCCAGAGTTTGGTACAGGCCAATTCCAAGTCATATGCCTAGTCTGCATAATATCCCAGTGCCTGAGACCAACTATCTAGGAAATACACCCACCATGCCATTCAGCTCCTTGCCACCAACAGATGAATCTATAAAATATACCATATACAATAGTACTGGCATTCAGATTGGAGCCTACAATTATATGGAGATTGGTGGGACGAGTTCATCACTACTAGACAGCACAAATACGAACTTCAAAGAAGAGCCAGCTGCTAAGTACCAAGCTATCTTTGATAATACCACTAGTCTGACGGATAAACACCTGGACCCAATCAGGGAAAATCTGGGAAAGCACTGGAAAAACTGTGCCCGTAAACTGGGCTTCACACAGTCTCAGATTGATGAAATTGACCATGACTATGAGCGAGATGGACTGAAAGAAAAGGTTTACCAGATGCTCCAAAAGTGGGTGATGAGGGAAGGCATAAAGGGAGCCACGGTGGGGAAGCTGGCCCAGGCGCTCCACCAGTGTTCCAGGATCGACCTTCTGAGCAGCTTGATTTA CGTCAGCCAGAACTAAHuman TRAF6 CDS (SEQ ID NO: 36)ATGAGTCTGCTAAACTGTGAAAACAGCTGTGGATCCAGCCAGTCTGAAAGTGACTGCTGTGTGGCCATGGCCAGCTCCTGTAGCGCTGTAACAAAAGATGATAGTGTGGGTGGAACTGCCAGCACGGGGAACCTCTCCAGCTCATTTATGGAGGAGATCCAGGGATATGATGTAGAGTTTGACCCACCCCTGGAAAGCAAGTATGAATGCCCCATCTGCTTGATGGCATTACGAGAAGCAGTGCAAACGCCATGCGGCCATAGGTTCTGCAAAGCCTGCATCATAAAATCAATAAGGGATGCAGGTCACAAATGTCCAGTTGACAATGAAATACTGCTGGAAAATCAACTATTTCCAGACAATTTTGCAAAACGTGAGATTCTTTCTCTGATGGTGAAATGTCCAAATGAAGGTTGTTTGCACAAGATGGAACTGAGACATCTTGAGGATCATCAAGCACATTGTGAGTTTGCTCTTATGGATTGTCCCCAATGCCAGCGTCCCTTCCAAAAATTCCATATTAATATTCACATTCTGAAGGATTGTCCAAGGAGACAGGTTTCTTGTGACAACTGTGCTGCATCAATGGCATTTGAAGATAAAGAGATCCATGACCAGAACTGTCCTTTGGCAAATGTCATCTGTGAATACTGCAATACTATACTCATCAGAGAACAGATGCCTAATCATTATGATCTAGACTGCCCTACAGCCCCAATTCCATGCACATTCAGTACTTTTGGTTGCCATGAAAAGATGCAGAGGAATCACTTGGCACGCCACCTACAAGAGAACACCCAGTCACACATGAGAATGTTGGCCCAGGCTGTTCATAGTTTGAGCGTTATACCCGACTCTGGGTATATCTCAGAGGTCCGGAATTTCCAGGAAACTATTCACCAGTTAGAGGGTCGCCTTGTAAGACAAGACCATCAAATCCGGGAGCTGACTGCTAAAATGGAAACTCAGAGTATGTATGTAAGTGAGCTCAAACGAACCATTCGAACCCTTGAGGACAAAGTTGCTGAAATCGAAGCACAGCAGTGCAATGGAATTTATATTTGGAAGATTGGCAACTTTGGAATGCATTTGAAATGTCAAGAAGAGGAGAAACCTGTTGTGATTCATAGCCCTGGATTCTACACTGGCAAACCCGGGTACAAACTGTGCATGCGCTTGCACCTTCAGTTACCGACTGCTCAGCGCTGTGCAAACTATATATCCCTTTTTGTCCACACAATGCAAGGAGAATATGACAGCCACCTCCCTTGGCCCTTCCAGGGTACAATACGCCTTACAATTCTTGATCAGTCTGAAGCACCTGTAAGGCAAAACCACGAAGAGATAATGGATGCCAAACCAGAGCTGCTTGCTTTCCAGCGACCCACAATCCCACGGAACCCAAAAGGTTTTGGCTATGTAACTTTTATGCATCTGGAAGCCCTAAGACAAAGAACTTTCATTAAGGATGACACATTATTAGTGCGCTGTGAGGTCTCCACCCGCTTTGACATGGGTAGCCTTCGGAGGGAGGGTTTTCAGCCACGAAG TACTGATGCAGGGGTATAGHuman TTP CDS (SEQ ID NO: 37)ATGGCCAACCGTTACACCATGGATCTGACTGCCATCTACGAGAGCCTCCTGTCGCTGAGCCCTGACGTGCCCGTGCCATCCGACCATGGAGGGACTGAGTCCAGCCCAGGCTGGGGCTCCTCGGGACCCTGGAGCCTGAGCCCCTCCGACTCCAGCCCGTCTGGGGTCACCTCCCGCCTGCCTGGCCGCTCCACCAGCCTAGTGGAGGGCCGCAGCTGTGGCTGGGTGCCCCCACCCCCTGGCTTCGCACCGCTGGCTCCCCGCCTGGGCCCTGAGCTGTCACCCTCACCCACTTCGCCCACTGCAACCTCCACCACCCCCTCGCGCTACAAGACTGAGCTATGTCGGACCTTCTCAGAGAGTGGGCGCTGCCGCTACGGGGCCAAGTGCCAGTTTGCCCATGGCCTGGGCGAGCTGCGCCAGGCCAATCGCCACCCCAAATACAAGACGGAACTCTGTCACAAGTTCTACCTCCAGGGCCGCTGCCCCTACGGCTCTCGCTGCCACTTCATCCACAACCCTAGCGAAGACCTGGCGGCCCCGGGCCACCCTCCTGTGCTTCGCCAGAGCATCAGCTTCTCCGGCCTGCCCTCTGGCCGCCGGACCTCACCACCACCACCAGGCCTGGCCGGCCCTTCCCTGTCCTCCAGCTCCTTCTCGCCCTCCAGCTCCCCACCACCACCTGGGGACCTTCCACTGTCACCCTCTGCCTTCTCTGCTGCCCCTGGCACCCCCCTGGCTCGAAGAGACCCCACCCCAGTCTGTTGCCCCTCCTGCCGAAGGGCCACTCCTATCAGCGTCTGGGGGCCCTTGGGTGGCCTGGTTCGGACCCCCTCTGTACAGTCCCTGGGATCCGACCCTGATGAATATGCCAGCAGCGGCAGCAGCCTGGGGGGCTCTGACTCTCCCGTCTTCGAGGCGGGAGTTTTTGCACCACCCCAGCCCGTGGCAGCCCCCCGGCGACTCCCCATCTTCAATCGCATCTCTGTTTCTGAGTGA

An antisense nucleic acid molecule can be complementary to all or partof a non-coding region of the coding strand of a nucleotide sequenceencoding an AP-1, ASK1, CD14, c-jun, ERK1/2, IκB, IKK, IRAK, JNK, LBP,MAPK, MEK1/2, MEKK1/4, MEKK4/7, MEKK 3/6, MK2, MyD88, NF-κB, NIK, p38,PKR, rac, ras, raf, RIP, TNFα, TNFR1, TNFR2, TRADD, TRAF2, TRAF6, orTTPMEKK1 protein. Non-coding regions (5′ and 3′ untranslated regions)are the 5′ and 3′ sequences that flank the coding region in a gene andare not translated into amino acids.

Based upon the sequences disclosed herein, one of skill in the art caneasily choose and synthesize any of a number of appropriate antisensenucleic acids to target a nucleic acid encoding an AP-1, ASK1, CD14,c-jun, ERK1/2, IκB, IKK, IRAK, JNK, LBP, MAPK, MEK1/2, MEKK1/4, MEKK4/7,MEKK 3/6, MK2, MyD88, NF-κB, NIK, p38, PKR, rac, ras, raf, RIP, TNFα,TNFR1, TNFR2, TRADD, TRAF2, TRAF6, or TTP protein described herein.Antisense nucleic acids targeting a nucleic acid encoding an AP-1, ASK1,CD14, c-jun, ERK1/2, IκB, IKK, IRAK, JNK, LBP, MAPK, MEK1/2, MEKK1/4,MEKK4/7, MEKK 3/6, MK2, MyD88, NF-κB, NIK, p38, PKR, rac, ras, raf, RIP,TNFα, TNFR1, TNFR2, TRADD, TRAF2, TRAF6, or TTPMEKK1 protein can bedesigned using the software available at the Integrated DNA Technologieswebsite.

An antisense nucleic acid can be, for example, about 5, 10, 15, 18, 20,22, 24, 25, 26, 28, 30, 32, 35, 36, 38, 40, 42, 44, 45, 46, 48, or 50nucleotides or more in length. An antisense oligonucleotide can beconstructed using enzymatic ligation reactions and chemical synthesisusing procedures known in the art. For example, an antisense nucleicacid can be chemically synthesized using variously modified nucleotidesor naturally occurring nucleotides designed to increase the physicalstability of the duplex formed between the antisense and sense nucleicacids, e.g., phosphorothioate derivatives and acridine substitutednucleotides or to increase the biological stability of the molecules.

Examples of modified nucleotides which can be used to generate anantisense nucleic acid include 1-methylguanine, 1-methylinosine,2,2-dimethylguanine, 2-methyladenine, 2-methylguanine, 3-methylcytosine,2-methylthio-N6-isopentenyladenine, uracil-5-oxyacetic acid (v),wybutoxosine, pseudouracil, queosine, 2-thiocytosine, 5-fluorouracil,5-bromouracil, 5-chlorouracil, 5-iodouracil, hypoxanthine, xanthine,4-acetylcytosine, 5-(carboxyhydroxylmethyl) uracil,5-carboxymethylaminomethyl-2-thiouridine,5-carboxymethylaminomethyluracil, dihydrouracil,beta-D-galactosylqueosine, inosine, N6-isopentenyladenine,5-methylcytosine, N6-adenine, 7-methylguanine,5-methylaminomethyluracil, 5-methoxyaminomethyl-2-thiouracil,beta-D-mannosylqueosine, 5′-methoxycarboxymethyluracil, 5-methoxyuracil,5-methyl-2-thiouracil, 2-thiouracil, 4-thiouracil, 5-methyluracil,uracil-5-oxyacetic acid methylester, uracil-5-oxyacetic acid (v),5-methyl-2-thiouracil, 3-(3-amino-3-N-2-carboxypropyl) uracil, (acp3)w,and 2,6-diaminopurine. Alternatively, the antisense nucleic acid can beproduced biologically using an expression vector into which a nucleicacid has been subcloned in an antisense orientation (i.e., RNAtranscribed from the inserted nucleic acid will be of an antisenseorientation to a target nucleic acid of interest).

The antisense nucleic acid molecules described herein can be prepared invitro and administered to a subject, e.g., a human subject.Alternatively, they can be generated in situ such that they hybridizewith or bind to cellular mRNA and/or genomic DNA encoding an AP-1, ASK1,CD14, c-jun, ERK1/2, IκB, IKK, IRAK, JNK, LBP, MAPK, MEK1/2, MEKK1/4,MEKK4/7, MEKK 3/6, MK2, MyD88, NF-κB, NIK, p38, PKR, rac, ras, raf, RIP,TNFα, TNFR1, TNFR2, TRADD, TRAF2, TRAF6, or TTP protein to therebyinhibit expression, e.g., by inhibiting transcription and/ortranslation. The hybridization can be by conventional nucleotidecomplementarities to form a stable duplex, or, for example, in the caseof an antisense nucleic acid molecule that binds to DNA duplexes,through specific interactions in the major groove of the double helix.The antisense nucleic acid molecules can be delivered to a mammaliancell using a vector (e.g., an adenovirus vector, a lentivirus, or aretrovirus).

An antisense nucleic acid can be an α-anomeric nucleic acid molecule. Anα-anomeric nucleic acid molecule forms specific double-stranded hybridswith complementary RNA in which, contrary to the usual, (3-units, thestrands run parallel to each other (Gaultier et al., Nucleic Acids Res.15:6625-6641, 1987). The antisense nucleic acid can also comprise achimeric RNA-DNA analog (Inoue et al., FEBS Lett. 215:327-330, 1987) ora 2′-O-methylribonucleotide (Inoue et al., Nucleic Acids Res.15:6131-6148, 1987).

Another example of an inhibitory nucleic acid is a ribozyme that hasspecificity for a nucleic acid encoding an AP-1, ASK1, CD14, c-jun,ERK1/2, IκB, IKK, IRAK, JNK, LBP, MAPK, MEK1/2, MEKK1/4, MEKK4/7, MEKK3/6, MK2, MyD88, NF-κB, NIK, p38, PKR, rac, ras, raf, RIP, TNFα, TNFR1,TNFR2, TRADD, TRAF2, TRAF6, or TTP mRNA, e.g., specificity for any oneof SEQ ID NOs: 1-37). Ribozymes are catalytic RNA molecules withribonuclease activity that are capable of cleaving a single-strandednucleic acid, such as an mRNA, to which they have a complementaryregion. Thus, ribozymes (e.g., hammerhead ribozymes (described inHaselhoff and Gerlach, Nature 334:585-591, 1988)) can be used tocatalytically cleave mRNA transcripts to thereby inhibit translation ofthe protein encoded by the mRNA. An AP-1, ASK1, CD14, c-jun, ERK1/2,IκB, IKK, IRAK, JNK, LBP, MAPK, MEK1/2, MEKK1/4, MEKK4/7, MEKK 3/6, MK2,MyD88, NF-κB, NIK, p38, PKR, rac, ras, raf, RIP, TNFα, TNFR1, TNFR2,TRADD, TRAF2, TRAF6, or TTP mRNA can be used to select a catalytic RNAhaving a specific ribonuclease activity from a pool of RNA molecules.See, e.g., Bartel et al., Science 261:1411-1418, 1993.

Alternatively, a ribozyme having specificity for an AP-1, ASK1, CD14,c-jun, ERK1/2, IκB, IKK, IRAK, JNK, LBP, MAPK, MEK1/2, MEKK1/4, MEKK4/7,MEKK 3/6, MK2, MyD88, NF-κB, NIK, p38, PKR, rac, ras, raf, RIP, TNFα,TNFR1, TNFR2, TRADD, TRAF2, TRAF6, or TTP mRNA can be designed basedupon the nucleotide sequence of any of the AP-1, ASK1, CD14, c-jun,ERK1/2, IκB, IKK, IRAK, JNK, LBP, MAPK, MEK1/2, MEKK1/4, MEKK4/7, MEKK3/6, MK2, MyD88, NF-κB, NIK, p38, PKR, rac, ras, raf, RIP, TNFα, TNFR1,TNFR2, TRADD, TRAF2, TRAF6, or TTP mRNA sequences disclosed herein. Forexample, a derivative of a Tetrahymena L-19 IVS RNA can be constructedin which the nucleotide sequence of the active site is complementary tothe nucleotide sequence to be cleaved in an AP-1, ASK1, CD14, c-jun,ERK1/2, IκB, IKK, IRAK, JNK, LBP, MAPK, MEK1/2, MEKK1/4, MEKK4/7, MEKK3/6, MK2, MyD88, NF-κB, NIK, p38, PKR, rac, ras, raf, RIP, TNFα, TNFR1,TNFR2, TRADD, TRAF2, TRAF6, or TTP mRNA (see, e.g., U.S. Pat. Nos.4,987,071 and 5,116,742).

An inhibitory nucleic acid can also be a nucleic acid molecule thatforms triple helical structures. For example, expression of an AP-1,ASK1, CD14, c-jun, ERK1/2, IκB, IKK, IRAK, JNK, LBP, MAPK, MEK1/2,MEKK1/4, MEKK4/7, MEKK 3/6, MK2, MyD88, NF-κB, p38, PKR, rac, ras, raf,RIP, TNFα, TNFR1, TNFR2, TRADD, TRAF2, TRAF6, or TTP polypeptide can beinhibited by targeting nucleotide sequences complementary to theregulatory region of the gene encoding the AP-1, ASK1, CD14, c-jun,ERK1/2, IκB, IKK, IRAK, JNK, LBP, MAPK, MEK1/2, MEKK1/4, MEKK4/7, MEKK3/6, MK2, MyD88, NF-κB, NIK, p38, PKR, rac, ras, raf, RIP, TNFα, TNFR1,TNFR2, TRADD, TRAF2, TRAF6, or TTP polypeptide (e.g., the promoterand/or enhancer, e.g., a sequence that is at least 1 kb, 2 kb, 3 kb, 4kb, or 5 kb upstream of the transcription initiation start state) toform triple helical structures that prevent transcription of the gene intarget cells. See generally Maher, Bioassays 14(12):807-15, 1992;Helene, Anticancer Drug Des. 6(6):569-84, 1991; and Helene, Ann. N.Y.Acad. Sci. 660:27-36, 1992.

In various embodiments, inhibitory nucleic acids can be modified at thesugar moiety, the base moiety, or phosphate backbone to improve, e.g.,the solubility, stability, or hybridization, of the molecule. Forexample, the deoxyribose phosphate backbone of the nucleic acids can bemodified to generate peptide nucleic acids (see, e.g., Hyrup et al.,Bioorganic Medicinal Chem. 4(1):5-23, 1996). Peptide nucleic acids(PNAs) are nucleic acid mimics, e.g., DNA mimics, in which thedeoxyribose phosphate backbone is replaced by a pseudopeptide backboneand only the four natural nucleobases are retained. The neutral backboneof PNAs allows for specific hybridization to RNA and DNA underconditions of low ionic strength. PNA oligomers can be synthesized usingstandard solid phase peptide synthesis protocols (see, e.g.,Perry-O'Keefe et al., Proc. Natl. Acad. Sci. U.S.A. 93:14670-675, 1996).PNAs can be used as antisense or antigene agents for sequence-specificmodulation of gene expression by, e.g., inducing transcription ortranslation arrest or inhibiting replication.

Small Molecules

In some embodiments, the anti-TNFα agent is a small molecule. In someembodiments, the small molecule is a tumor necrosis factor-convertingenzyme (TACE) inhibitor (e.g., Moss et al., Nature Clinical PracticeRheumatology 4: 300-309, 2008). In some embodiments, the anti-TNFα agentis C₈₇ (Ma et al., J. Biol. Chem. 289(18):12457-66, 2014). In someembodiments, the small molecule is LMP-420 (e.g., Haraguchi et al., AIDSRes. Ther. 3:8, 2006). In some embodiments, the TACE inhibitor isTMI-005 and BMS-561392. Additional examples of small molecule inhibitorsare described in, e.g., He et al., Science 310(5750):1022-1025, 2005.

In some examples, the anti-TNFα agent is a small molecule that inhibitsthe activity of one of AP-1, ASK1, IKK, JNK, MAPK, MEKK 1/4, MEKK4/7,MEKK 3/6, NIK, TRADD, RIP, NF-κB, and TRADD in a cell (e.g., in a cellobtained from a subject, a mammalian cell).

In some examples, the anti-TNFα agent is a small molecule that inhibitsthe activity of one of CD14, MyD88 (see, e.g., Olson et al., ScientificReports 5:14246, 2015), ras (e.g., Baker et al., Nature 497:577-578,2013), raf (e.g., vemurafenib (PLX4032, RG7204), sorafenib tosylate,PLX-4720, dabrafenib (GSK2118436), GDC-0879, RAF265 (CHIR-265), AZ 628,NVP-BHG712, SB590885, ZM 336372, sorafenib, GW5074, TAK-632, CEP-32496,encorafenib (LGX818), CCT196969, LY3009120, R05126766 (CH5126766),PLX7904, and MLN2480).

In some examples, the anti-TNFα agent TNFα inhibitor is a small moleculethat inhibits the activity of one of MK2 (PF 3644022 and PHA 767491),JNK (e.g., AEG 3482, BI 78D3, CEP 1347, c-JUN peptide, IQ 15, JIP-1(153-163), SP600125, SU 3327, and TCS JNK6o), c-jun (e.g., AEG 3482, BI78D3, CEP 1347, c-JUN peptide, IQ 1S, JIP-1 (153-163), SP600125, SU3327, and TCS JNK6o), MEK3/6 (e.g., Akinleye et al., J. Hematol. Oncol.6:27, 2013), p38 (e.g., AL 8697, AMG 548, BIRB 796, CMPD-1, DBM 1285dihydrochloride, EO 1428, JX 401, ML 3403, Org 48762-0, PH 797804, RWJ67657, SB 202190, SB 203580, SB 239063, SB 706504, SCIO 469, SKF 86002,SX 011, TA 01, TA 02, TAK 715, VX 702, and VX 745), PKR (e.g.,2-aminopurine or CAS 608512-97-6), TTP (e.g., CAS 329907-28-0), MEK1/2(e.g., Facciorusso et al., Expert Review Gastroentrol. Hepatol.9:993-1003, 2015), ERK1/2 (e.g., Mandal et al., Oncogene 35:2547-2561,2016), NIK (e.g., Mortier et al., Bioorg. Med. Chem. Lett. 20:4515-4520,2010), IKK (e.g., Reilly et al., Nature Med. 19:313-321, 2013), IκB(e.g., Suzuki et al., Expert. Opin. Invest. Drugs 20:395-405, 2011),NF-κB (e.g., Gupta et al., Biochim. Biophys. Acta 1799(10-12):775-787,2010), rac (e.g., U.S. Pat. No. 9,278,956), MEK4/7, IRAK (Chaudhary etal., J. Med. Chem. 58(1):96-110, 2015), LBP (see, e.g., U.S. Pat. No.5,705,398), and TRAF6 (e.g.,3-[(2,5-Dimethylphenyl)amino]-1-phenyl-2-propen-1-one).

In some embodiments of any of the methods described herein, theinhibitory nucleic acid can be about 10 nucleotides to about 50nucleotides (e.g., about 10 nucleotides to about 45 nucleotides, about10 nucleotides to about 40 nucleotides, about 10 nucleotides to about 35nucleotides, about 10 nucleotides to about 30 nucleotides, about 10nucleotides to about 28 nucleotides, about 10 nucleotides to about 26nucleotides, about 10 nucleotides to about 25 nucleotides, about 10nucleotides to about 24 nucleotides, about 10 nucleotides to about 22nucleotides, about 10 nucleotides to about 20 nucleotides, about 10nucleotides to about 18 nucleotides, about 10 nucleotides to about 16nucleotides, about 10 nucleotides to about 14 nucleotides, about 10nucleotides to about 12 nucleotides, about 12 nucleotides to about 50nucleotides, about 12 nucleotides to about 45 nucleotides, about 12nucleotides to about 40 nucleotides, about 12 nucleotides to about 35nucleotides, about 12 nucleotides to about 30 nucleotides, about 12nucleotides to about 28 nucleotides, about 12 nucleotides to about 26nucleotides, about 12 nucleotides to about 25 nucleotides, about 12nucleotides to about 24 nucleotides, about 12 nucleotides to about 22nucleotides, about 12 nucleotides to about 20 nucleotides, about 12nucleotides to about 18 nucleotides, about 12 nucleotides to about 16nucleotides, about 12 nucleotides to about 14 nucleotides, about 15nucleotides to about 50 nucleotides, about 15 nucleotides to about 45nucleotides, about 15 nucleotides to about 40 nucleotides, about 15nucleotides to about 35 nucleotides, about 15 nucleotides to about 30nucleotides, about 15 nucleotides to about 28 nucleotides, about 15nucleotides to about 26 nucleotides, about 15 nucleotides to about 25nucleotides, about 15 nucleotides to about 24 nucleotides, about 15nucleotides to about 22 nucleotides, about 15 nucleotides to about 20nucleotides, about 15 nucleotides to about 18 nucleotides, about 15nucleotides to about 16 nucleotides, about 16 nucleotides to about 50nucleotides, about 16 nucleotides to about 45 nucleotides, about 16nucleotides to about 40 nucleotides, about 16 nucleotides to about 35nucleotides, about 16 nucleotides to about 30 nucleotides, about 16nucleotides to about 28 nucleotides, about 16 nucleotides to about 26nucleotides, about 16 nucleotides to about 25 nucleotides, about 16nucleotides to about 24 nucleotides, about 16 nucleotides to about 22nucleotides, about 16 nucleotides to about 20 nucleotides, about 16nucleotides to about 18 nucleotides, about 18 nucleotides to about 20nucleotides, about 20 nucleotides to about 50 nucleotides, about 20nucleotides to about 45 nucleotides, about 20 nucleotides to about 40nucleotides, about 20 nucleotides to about 35 nucleotides, about 20nucleotides to about 30 nucleotides, about 20 nucleotides to about 28nucleotides, about 20 nucleotides to about 26 nucleotides, about 20nucleotides to about 25 nucleotides, about 20 nucleotides to about 24nucleotides, about 20 nucleotides to about 22 nucleotides, about 24nucleotides to about 50 nucleotides, about 24 nucleotides to about 45nucleotides, about 24 nucleotides to about 40 nucleotides, about 24nucleotides to about 35 nucleotides, about 24 nucleotides to about 30nucleotides, about 24 nucleotides to about 28 nucleotides, about 24nucleotides to about 26 nucleotides, about 24 nucleotides to about 25nucleotides, about 26 nucleotides to about 50 nucleotides, about 26nucleotides to about 45 nucleotides, about 26 nucleotides to about 40nucleotides, about 26 nucleotides to about 35 nucleotides, about 26nucleotides to about 30 nucleotides, about 26 nucleotides to about 28nucleotides, about 28 nucleotides to about 50 nucleotides, about 28nucleotides to about 45 nucleotides, about 28 nucleotides to about 40nucleotides, about 28 nucleotides to about 35 nucleotides, about 28nucleotides to about 30 nucleotides, about 30 nucleotides to about 50nucleotides, about 30 nucleotides to about 45 nucleotides, about 30nucleotides to about 40 nucleotides, about 30 nucleotides to about 38nucleotides, about 30 nucleotides to about 36 nucleotides, about 30nucleotides to about 34 nucleotides, about 30 nucleotides to about 32nucleotides, about 32 nucleotides to about 50 nucleotides, about 32nucleotides to about 45 nucleotides, about 32 nucleotides to about 40nucleotides, about 32 nucleotides to about 35 nucleotides, about 35nucleotides to about 50 nucleotides, about 35 nucleotides to about 45nucleotides, about 35 nucleotides to about 40 nucleotides, about 40nucleotides to about 50 nucleotides, about 40 nucleotides to about 45nucleotides, about 42 nucleotides to about 50 nucleotides, about 42nucleotides to about 45 nucleotides, or about 45 nucleotides to about 50nucleotides) in length. One skilled in the art will appreciate thatinhibitory nucleic acids may comprises at least one modified nucleicacid at either the 5′ or 3′ end of DNA or RNA.

In some embodiments, the inhibitory nucleic acid can be formulated in aliposome, a micelle (e.g., a mixed micelle), a nanoemulsion, or amicroemulsion, a solid nanoparticle, or a nanoparticle (e.g., ananoparticle including one or more synthetic polymers). Additionalexemplary structural features of inhibitory nucleic acids andformulations of inhibitory nucleic acids are described in US2016/0090598.

In some embodiments, the inhibitory nucleic acid (e.g., any of theinhibitory nucleic acid described herein) can include a sterile salinesolution (e.g., phosphate-buffered saline (PBS)). In some embodiments,the inhibitory nucleic acid (e.g., any of the inhibitory nucleic aciddescribed herein) can include a tissue-specific delivery molecule (e.g.,a tissue-specific antibody).

Compound Preparation and Biological Assays

As can be appreciated by the skilled artisan, methods of synthesizingthe compounds of the formulae herein will be evident to those ofordinary skill in the art. Synthetic chemistry transformations andprotecting group methodologies (protection and deprotection) useful insynthesizing the compounds described herein are known in the art andinclude, for example, those such as described in R. Larock,Comprehensive Organic Transformations, VCH Publishers (1989); T. W.Greene and RGM. Wuts, Protective Groups in Organic Synthesis, 2d. Ed.,John Wiley and Sons (1991); L. Fieser and M. Fieser, Fieser and Fieser'sReagents for Organic Synthesis, John Wiley and Sons (1994); and L.Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, JohnWiley and Sons (1995), and subsequent editions thereof.

PREPARATIVE EXAMPLES

The following abbreviations have the indicated meanings:

-   ACN=acetonitrile-   BTC=trichloromethyl chloroformate-   Boc=t-butyloxy carbonyl-   Davephos=cyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl-   DCM=dichloromethane-   DEA=diethylamine-   DMF=N,N-dimethylformamide-   DMSO=dimethyl sulfoxide-   DIEA=N,N-diisopropylethylamine-   DPPA=diphenylphosphoryl azide-   dppf=1,1′-Bis(diphenylphosphino)ferrocene-   EtOH=ethanol-   HATU=1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium    3-oxid hexafluorophosphate-   Hex=hexane-   HPLC=high performance liquid chromatography-   LC-MS=liquid chromatography-mass spectrometry-   LiHMDS=lithium bis(trimethylsilyl)amide-   LDA=lithium diisopropylamide-   M=mol/L-   Me=methyl-   MeOH=methanol-   MSA=methanesulfonic acid-   NBS=N-bromosuccinimide-   NCS=N-chlorosuccinimide-   NMR=nuclear magnetic resonance-   Pd(dppf)Cl₂=dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium-   Ph=phenyl-   PPh₃Cl₂=dichlorotriphenylphosphorane-   Py=pyridine-   RT=room temperature-   Rt=Retention time-   R_(f)=Retardation factor-   Sat.=saturated-   TBAF=tetrabutylammonium fluoride-   TBS=tert-butyldimethylsilyl-   TBSCl=tert-butyldimethylsilyl chloride-   TBDPSCl=tert-butyldiphenylsilyl chloride-   TEA=triethylamine-   TFA=trifluoroacetic acid-   THF=tetrahydrofuran-   TLC=thin layer chromatography-   TsOH=4-methylbenzenesulfonic acid-   UV=ultraviolet

General

The progress of reactions was often monitored by TLC or LC-MS. Theidentity of the products was often confirmed by LC-MS. The LC-MS wasrecorded using one of the following methods.

Method A: Shim-pack XR-ODS, C18, 3×50 mm, 2.5 um column, 1.0 uLinjection, 1.5 mL/min flow rate, 90-900 amu scan range, 190-400 nm UVrange, 5-100% (1.1 min), 100% (0.6 min) gradient with ACN (0.05% TFA)and water (0.05% TFA), 2 minute total run time.

Method B: Kinetex EVO, C18, 3×50 mm, 2.2 um column, 1.0 uL injection,1.5 mL/min flow rate, 90-900 amu scan range, 190-400 nm UV range, 10-95%(1.1 min), 95% (0.6 min) gradient with ACN and water (0.5% NH₄HCO3), 2minute total run time.

Method C: Shim-pack XR-ODS, C18, 3×50 mm, 2.5 um column, 1.0 uLinjection, 1.5 mL/min flow rate, 90-900 amu scan range, 190-400 nm UVrange, 5-100% (2.1 min), 100% (0.6 min) gradient with ACN (0.05% TFA)and water (0.05% TFA), 3 minute total run time.

Method D: Kinetex EVO, C18, 3×50 mm, 2.2 um column, 1.0 uL injection,1.5 mL/min flow rate, 90-900 amu scan range, 190-400 nm UV range, 10-95%(2.1 min), 95% (0.6 min) gradient with ACN and water (0.5% NH₄HCO3), 3minute total run time.

Method F: Phenomenex, CHO-7644, Onyx Monolithic C18, 50×4.6 mm, 10.0 uLinjection, 1.5 mL/min flow rate, 100-1500 amu scan range, 220 and 254 nmUV detection, 5% with ACN (0.1% TFA) to 100% water (0.1% TFA) over 9.5min, with a stay at 100% (ACN, 0.1% TFA) for 1 min, then equilibrationto 5% (ACN, 0.1% TFA) over 1.5 min.

The final targets were purified by Prep-HPLC. The Prep-HPLC was carriedout using the following method.

Method E: Prep-HPLC: Column, XBridge Shield RP18 OBD (19×250 mm, 10 um);mobile phase, Water (10 mmol/L NH₄HCO₃) and ACN, UV detection 254/210nm.

Method G: Prep-HPLC: Higgins Analytical Proto 200, C18 Column, 250×20mm, 10 um; mobile phase, Water (0.1% TFA) and ACN (0.1% TFA), UVdetection 254/210 nm.

NMR was recorded on BRUKER NMR 300.03 MHz, DUL-C-H, ULTRASHIELD™ 300,AVANCE II 300 B-ACS™ 120 or BRUKER NMR 400.13 MHz, BBFO, ULTRASHIELD™400, AVANCE III 400, B-ACS™ 120 or BRUKER AC 250 NMR instrument with TMSas reference measured in ppm (part per million).

Racemic compounds of this invention can be resolved to give individualenantiomers using a variety of known methods. For example, chiralstationary phases can used and the elution conditions can include normalphase or super-critical fluid with or without acidic or basic additives.Enantiomerically pure acids or bases can be used to form diatereomericsalts with the racemic compounds whereby pure enantiomers can beobtained by fractional crystallization. The racemates can also bederivatized with enantiomerically pure auxiliary reagents to formdiastereomeric mixtures that can be separated. The auxiliary is thenremoved to give pure enantiomers.

Schemes for the Preparation of Final Targets:

Schemes 1-3 below illustrate several conditions used for coupling ofsulfonimidamide 1 or 5 and isocyanate 2 to afford aminocarbonylsulfonimidamide 4 via 3 or 6 after deprotection. As used in the schemes,rings “A” and “B” may be substituted as disclosed herein.

Scheme 4 below illustrates the coupling between sulfonimidamide 7 andisocyanate 2 to provide sulfonimidamide 8.

Scheme 5 below illustrates the conversion of carboxylic acid 9 throughCurtius rearrangement to isocyanate 2 via acyl azide 10, whereuponcoupling between 2 and sulfonimidamide 5 affords aminocarbonylsulfonimidamide 4.

Schemes for the Preparation of Sulfonimidamide Intermediates 1-29:

Schemes below illustrate the preparation of sulfonamide intermediates.

N′-(tert-butyl dim ethylsilyl)-4-(2-hydroxypropan-2-yl)-5-methylfuran-2-sulfonimidamide Step 1:Methyl 5-(chlorosulfonyl)-2-methylfuran-3-carboxylate

Into a 500-mL 3-necked round-bottom flask was placed methyl2-methylfuran-3-carboxylate (7 g, 50 mmol) in CHCl₃ (200 mL). This wasfollowed by the addition of chlorosulfonic acid (11.6 g, 100 mmol)dropwise with stirring at −10° C. The reaction mixture was stirred for48 h at RT, after which the system was cooled to −10° C. Then to theabove was added phosphorus pentachloride (22.9 g, 110 mmol). Theresulting solution was stirred for 0.5 h at 50° C. and then was quenchedby pouring onto 200 mL of water/ice. The resulting mixture was extractedwith 3×200 mL of DCM. The organic layers were combined and dried overanhydrous Na₂SO₄, and then concentrated under vacuum. This resulted in7.5 g (crude, 63%) of the title compound as light brown oil. The crudeproduct was used in the next step.

Step 2: Methyl 2-methyl-5-sulfamoylfuran-3-carboxylate

Into a 250-mL round-bottom flask was placed a solution of methyl5-(chlorosulfonyl)-2-methylfuran-3-carboxylate (7.5 g, crude) in DCM (75mL). To the above was added a saturated solution of ammonia in DCM (50mL). The resulting solution was stirred for 3 h at RT and then wasconcentrated under vacuum. The residue was applied onto a silica gelcolumn and eluted with a gradient of ethyl acetate/petroleum ether (1:4to 1:2). This resulted in 5.0 g (46% over two steps) of the titlecompound as a light yellow solid. MS-ESI: 218.0 (M−1).

Step 3: 4-(2-Hydroxypropan-2-yl)-5-methylfuran-2-sulfonamide

Into a 250-mL 3-necked round-bottom flask purged with and maintainedunder nitrogen was placed a solution of methyl2-methyl-5-sulfamoylfuran-3-carboxylate (3.7 g, 16.9 mmol) in THF (100mL). This was followed by the addition of MeMgBr (3 M in THF, 25 mL)dropwise with stirring at −10° C. The resulting mixture was stirred for10 h at RT and then was quenched by the addition of 50 mL of NH₄Cl(sat.). The resulting solution was extracted with 3×50 mL of ethylacetate. The organic layers were combined and dried over anhydrousNa₂SO₄, then concentrated under vacuum. The residue was applied onto asilica gel column and eluted with a gradient of ethyl acetate/petroleumether (1:3 to 1:1). This resulted in 2.6 g (75%) of the title compoundas a light yellow solid. MS-ESI: 218.0 (M−1).

Step 4:N-(tert-butyldimethylsilyl)-4-(2-hydroxypropan-2-yl)-5-methylfuran-2-sulfonamide

Into a 250-mL round-bottom flask purged with and maintained undernitrogen was placed 4-(2-hydroxypropan-2-yl)-5-methylfuran-2-sulfonamide(1.0 g, 4.56 mmol), DCM (100 mL), 1H-imidazole (612 mg, 9.12 mmol), andTBSCl (3.4 g, 22.6 mmol). The resulting solution was stirred for 14 h atRT and then was diluted with 100 mL of water. The resulting mixture wasextracted with 3×50 mL of DCM and the organic layers were combined andconcentrated under vacuum. The residue was applied onto a silica gelcolumn and eluted with a gradient of ethyl acetate/petroleum ether (1:10to 1:3). This resulted in 1.4 g (92%) of the title compound as a whitesolid. MS-ESI: 332.0 (M−1).

Step 5:N′-(tert-butyldimethylsilyl)-4-(2-hydroxypropan-2-yl)-5-methylfuran-2-sulfonimidamide

Into a 250-mL 3-necked round-bottom flask purged with and maintainedunder nitrogen was placed PPh₃Cl₂ (3.0 g, 10.2 mmol) in CHCl₃ (100 mL).This was followed by the addition of TEA (2.06 g, 20.4 mmol) dropwisewith stirring at RT. After stirred at 0° C. for 10 min, to the above wasadded a solution ofN-(tert-butyldimethylsilyl)-4-(2-hydroxypropan-2-yl)-5-methylfuran-2-sulfonamide(2.3 g, 6.8 mmol) in CHCl₃ (10 mL) dropwise with stirring at 0° C. Theresulting solution was allowed to react for 30 min at 0° C. To themixture was added a saturated solution of ammonia in DCM (10 mL) at 0°C. The resulting solution was stirred for 2 h at RT. The reaction wasthen quenched by the addition of 100 mL of water. The resulting solutionwas extracted with 3×50 mL of DCM and the organic layers combined andconcentrated under vacuum. The residue was applied onto a silica gelcolumn and eluted with a gradient of ethyl acetate/petroleum ether (1:10to 1:3). This resulted in 0.80 g (52.8%) of the title compound as alight yellow solid. MS-ESI: 333.0 (M+1).

N′-(tert-butyldimethylsilyl)-5-(2-hydroxypropan-2-yl)thiazole-2-sulfonimidamideStep 1: Methyl 2-mercaptothiazole-5-carboxylate

Into a 250-mL round-bottom flask was placed methyl2-bromothiazole-5-carboxylate (10 g, 45 mmol), EtOH (100 mL), and sodiumhydrogensulfide (5 g, 89 mmol). The resulting solution was stirred for 2h at 80° C. and then was cooled to 0° C. with a water/ice bath. The pHvalue of the solution was adjusted to 3 with aq. HCl (1 N). The solidswere collected by filtration. This resulted in 6 g (76%) of the titlecompound as a light yellow solid. MS-ESI: 176.0 (M+1).

Step 2: Methyl 2-(chlorosulfonyl)thiazole-5-carboxylate

Into a 250-mL round-bottom flask was placed methyl2-mercaptothiazole-5-carboxylate (6 g, 34 mmol) and acetic acid (60 mL).This was followed by the addition of sodium hypochlorite (60 mL, 8%-10%wt.) in portions at 0° C. The resulting solution was stirred for 1 h atRT and then was diluted with 100 mL of water. The solution was extractedwith 3×50 mL of DCM. The organic layers were combined and dried overanhydrous Na₂SO₄, then concentrated under vacuum. This resulted in 5 g(crude, 60%) of the title compound as yellow oil. The crude product wasused in the next step.

Step 3-6 used similar procedure for converting compound 12 toIntermediate 1 shown in Scheme 6 to afford Intermediate 2. MS-ESI: 336.1(M+1)

N′-(tert-butyl di methyl silyl)-5-(2-hydroxypropan-2-yl)thiazole-2-sulfonimidamide

Step 1: Methyl 2-mercaptothiazole-5-carboxylate

Into a 2-L round-bottom flask was placed methyl2-bromothiazole-5-carboxylate (100 g, 450 mmol), EtOH (1000 mL), sodiumhydrogensulfide (50 g, 890 mmol). The resulting solution was stirred for2 h at 80° C. and then was cooled to 0° C. with a water/ice bath. The pHvalue of the solution was adjusted to 3 with hydrogen chloride (1 N).The solids were collected by filtration. This resulted in 63.2 g (80%)of the title compound as a light yellow solid. MS-ESI: 176.0 (M+1).

Step 2: Methyl 2-(chlorosulfonyl)thiazole-5-carboxylate

Into a 1-L round-bottom flask was placed methyl2-mercaptothiazole-5-carboxylate (30 g, 170 mmol) and acetic acid (300mL). This was followed by the addition of sodium hypochlorite (300 mL,8%-10% wt.) in portions at 0° C. The resulting solution was stirred for2 h at RT and then was diluted with 500 mL of water. The solution wasextracted with 3×300 mL of DCM and the combined organic layers werewashed with 2×300 mL of brine and dried over anhydrous Na₂SO₄. The crudeproduct as a yellow solution in DCM was used in the next step.

Step 3: Methyl 2-sulfamoylthiazole-5-carboxylate

Into a 2-L round-bottom flask was placed methyl2-(chlorosulfonyl)thiazole-5-carboxylate as a crude solution in DCM (900mL). To the solution was introduced NH₃ (g) below 0° C. for 20 minutes.The resulting solution was stirred for 1 h at RT and then concentratedunder vacuum. The residue was applied onto a silica gel column andeluted with ethyl acetate/petroleum ether (1:5 to 1:3). This resulted in23 g (75%, 2 steps) of the title compound as a white solid. MS-ESI:223.0 (M+1).

Step 4: 5-(2-Hydroxypropan-2-yl)thiazole-2-sulfonamide

Into a 500-mL round-bottom flask purged with and maintained undernitrogen was placed a solution of methyl2-sulfamoylthiazole-5-carboxylate (15 g, 67.5 mmol) in THF (150 mL).This was followed by the addition of MeMgBr/THF (3 M, 90 mL) dropwisewith stirring at 0° C. The resulting solution was stirred for 14 h at RTand then was quenched by the addition of 100 mL of NH₄Cl (sat.). Theresulting solution was extracted with 3×150 mL of DCM. The organiclayers were combined and dried over anhydrous Na₂SO₄, then concentratedunder vacuum. The residue was applied onto a silica gel column andeluted with ethyl acetate/petroleum ether (1:5 to 1:3). This resulted in11.5 g (78%) of the title compound as a white solid. MS-ESI: 223.0(M+1), 221.0 (M−1) in positive and negative ion mode, respectively.

Step 5:N-(tert-butyldimethylsilyl)-5-(2-hydroxypropan-2-yl)thiazole-2-sulfonamide

Into a 250-mL 3-necked round-bottom flask purged with and maintainedunder nitrogen was placed a solution of5-(2-hydroxypropan-2-yl)thiazole-2-sulfonamide (5 g, 22.5 mmol) in THF(100 mL). Then to the above was added NaH (60% wt, 1.8 g, 45.0 mmol) inportions in an ice/water bath. After stirring for 20 minutes in awater/ice bath, this was followed by the addition of a solution of TBSCl(4.1 g, 27.2 mmol) in THF (10 mL) dropwise with stirring at 0° C. Theresulting solution was stirred for 4 h at RT. The reaction was quenchedwith sat. NH₄Cl (100 mL). The resulting solution was extracted with3×100 mL of ethyl acetate and the combined organic layers were driedover Na₂SO₄ and concentrated under vacuum. The crude solid was washedwith ethyl acetate/hexane (1:5) (2×100 mL). This resulted in 6.81 g(90%) of the title compound as a yellow solid. MS-ESI: 337.1 (M+1),335.1 (M−1) in positive and negative ion mode, respectively.

Step 6:N′-(tert-butyldimethylsilyl)-5-(2-hydroxypropan-2-yl)thiazole-2-sulfonimidamide

Into a 100-mL 3-necked round-bottom flask purged with and maintainedunder nitrogen was placed a solution of PPh₃Cl₂ (3 g, 9.0 mmol) in CHCl₃(100 mL). This was followed by the addition of DIEA (1.54 g, 11.9 mmol)dropwise with stirring at RT. The resulting solution was stirred for 10min at RT. This was followed by the addition of a solution ofN-(tert-butyldimethylsilyl)-5-(2-hydroxypropan-2-yl)thiazole-2-sulfonamide(2.0 g, 5.9 mmol) in CHCl₃ (30 mL) dropwise with stirring in anice/water bath. The resulting solution was stirred for 30 min in anice/water bath. To the above was introduced NH₃ (g) below 0° C. for 15minutes. The resulting solution was stirred for 20 minutes at RT. Thesolids were filtered out and the filtrate was concentrated and theresidue was dissolved in 300 mL of ethyl acetate. The solution waswashed with brine (2×100 mL), dried over Na₂SO₄ and concentrated undervacuum. The crude solid was washed with CHCl₃ (100 mL). Then thefiltrate was concentrated under vacuum and the residue was furtherpurified by a silica gel column with ethyl acetate/petroleum ether (1:10to 1:3). The original washed solid and solid from silica gelpurification were combined. This resulted in 1.2 g (60%) of the titlecompound as a white solid. MS-ESI: 336.1 (M+1). ¹H-NMR (300 MHz,DMSO-d6) δ 7.66 (s, 1H), 7.12 (s, 2H), 5.78 (s, 1H), 1.51 (s, 6H), 0.86(s, 9H), 0.02 (s, 3H), 0.01 (s, 3H).

TABLE 2 The Intermediate in the following Table was prepared using thesimilar procedures for converting compound 16 to Intermediate 2 shown inScheme 7B starting from ethyl 5-bromo-4-methylthiazole-2-carboxylate.Exact Intermediate # Structure IUPAC Name Mass[M + H]⁺ Intermediate 3

N′-(tert-butyldimethylsilyl)-2-(2- hydroxypropan-2-yl)-4-methylthiazole-5-sulfonimidamide 350.2

N′-(tert-butyldimethylsilyl)-4-(2-hydroxypropan-2-yl)-5-methylthiophene-2-sulfonimidamide

Steps 1-3 used similar procedures for converting compound 11 to compound14 shown in Scheme 6 to afford compound 25 from compound 22. MS-ESI:234.0 (M−1).

Steps 4-5 used similar procedure for converting compound 20 toIntermediate 2 shown in Scheme 7B to afford Intermediate 4 from compound25. MS-ESI: 349.1 (M+1).

TABLE 3 The Intermediate in the following Table was prepared usingsimilar procedure as shown in Scheme 8 above for converting compound 22to Intermediate 4 starting from the appropriate materials. ExactIntermediate # Structure IUPAC Name Mass[M + H]⁺ Intermediate 5

N′-(tert-butyldimethylsilyl)-5-(2- hydroxypropan-2-yl)thiophene-2-sulfonimidamide 335.1 Intermediate 6

N′-(tert-butyldimethylsilyl)-4-(2- hydroxypropan-2-yl)thiophene-2-sulfonimidamide 335.1 Intermediate 7

N′-(tert-butyldimethylsilyl)-5-(2- hydroxypropan-2-yl)-3-methylthiophene-2-sulfonimidamide 349.1 Intermediate 8

N′-(tert-butyldimethylsilyl)-5-(2- hydroxypropan-2-yl)-4-methylthiophene-2-sulfonimidamide 349.1 Intermediate 9

N′-(tert-butyldimethylsilyl)-3-fluoro-5-(2-hydroxypropan-2-yl)thiophene- 2-sulfonimidamide 353.1 Intermediate10

N′-(tert-butyldimethylsilyl)-4-(2- hydroxypropan-2-yl)furan-2-sulfonimidamide 319.1

N′-(tert-butyldimethyl silyl)-2-fluoro-4-(2-hydroxypropan-2-yl)benzenesulfonimidamide Step 1: Methyl 4-(chlorosulfonyl)-3-fluorobenzoate

Into a 1 L round-bottom flask was placed a solution of methyl4-amino-3-fluorobenzoate (10 g, 59.1 mmol) in aq. HCl (6 N, 200 mL).This was followed by the addition of a solution of NaNO₂ (6.1 g, 88.8mmol) in water (20 mL) dropwise with stirring at 0° C. The resultingsolution was stirred for 30 min at 0° C. The above mixture was added toa saturated solution of SO₂ in AcOH (200 mL) dropwise with stirring at0° C. Then to the above was added CuCl₂ (8.0 g, 59.6 mmol). Theresulting solution was stirred for 1 h at RT and was then quenched bythe addition of 200 mL of water. The resulting solution was extractedwith 3×200 mL of DCM. The organic layers were combined, dried overanhydrous Na₂SO₄ and concentrated under vacuum. This resulted in 10 g(67%) of the title compound as yellow oil. The product was used in thenext step without further purification.

Step 2: Methyl 3-fluoro-4-sulfamoylbenzoate

Into a 1000 mL round bottom flask was placed a solution of methyl4-(chlorosulfonyl)-3-fluorobenzoate solution (10 g, 39.5 mmol) in DCM(50 mL). This was followed by the addition of a saturated solution ofammonia in DCM (500 mL) in portions with stirring at 0° C. The resultingsolution was stirred for 1 h at 0° C. The resulting solution wasconcentrated and the residue was purified with SiO₂-gel column anddiluted with ethyl acetate/petroleum ether (1:2 to 1:1). This resultedin 8.28 g (90%) of the title compound as yellow solid. MS-ESI: 232.1(M−1).

Step 3: 2-Fluoro-4-(2-hydroxypropan-2-yl)benzenesulfonamide

Into a 1 L 3-necked round-bottom flask was placed a solution of methyl3-fluoro-4-sulfamoylbenzoate (8.28 g 35.5 mmol) in THF (500 mL). Thiswas followed by the addition of MeMgBr/THF (3 M, 60 mL) dropwise withstirring at 0° C. The resulting solution was stirred overnight at RT andthen was quenched by the addition of 100 mL of sat. NH₄C₁. The resultingsolution was extracted with 3×200 mL of ethyl acetate and the combinedorganic layers were concentrated under vacuum. The residue was appliedonto a silica gel column and eluted with ethyl acetate/petroleum ether(1:2 to 1:1). This resulted 7.45 g (89.9%) of the title compound as awhite solid. MS-ESI: 233.1 (M+1).

Step 4:N-(tert-butyldimethylsilyl)-2-fluoro-4-(2-hydroxypropan-2-yl)benzenesulfonamide

Into a 500 mL round bottom flask was placed a solution of2-fluoro-4-(2-hydroxypropan-2-yl)benzenesulfonamide (7.45 g 31.9 mmol)in THF (200 mL). This was followed by the addition of NaH (60% wt, 1.91g, 79.6 mmol). The mixture was stirred at 0° C. for 0.5 h. This wasfollowed by the addition of the solution of TBSC1 (7.19 g, 47.9 mmol) inTHF (50 mL) dropwise. The resulting solution was stirred at RTovernight. The reaction was quenched with ice-water (100 mL); theresulting solution was extracted with EtOAc (3×200 mL). The combinedorganic layers were dried over anhydrous Na₂SO₄ and concentrated undervacuum. The residue was purified with SiO₂-gel column and eluted withethyl acetate/petroleum ether (1:5 to 1:2). This resulted 10 g (90%) ofthe title compound as a white solid. MS-ESI: 348.1 (M+1).

Step 5:N′-(tert-butyldimethylsilyl)-2-fluoro-4-(2-hydroxypropan-2-yl)benzenesulfonimidamide

Into a 1 L 3-necked round-bottom flask purged with and maintained undernitrogen was placed a solution of PPh₃Cl₂ (19.2 g, 57.6 mmol) in CHCl₃(100 mL). This was followed by the addition of DIEA (7.4 g, 57.6 mmol)dropwise with stirring at 0° C. After stirred at 0° C. for 10 min, tothe above was added a solution ofN′-(tert-butyldimethylsilyl)-2-fluoro-4-(2-hydroxypropan-2-yl)benzenesulfonimidamide(10 g, 28.8 mmol) in CHCl₃ (100 mL) dropwise with stirring at 0° C. Theresulting solution was allowed to react for 30 min at 0° C. To themixture was added a saturated solution of ammonia in DCM (500 mL) at 0°C. The resulting solution was stirred for 2 h at RT. The solids werefiltered out, and the filtrate was dilute with 100 mL of water. Theresulting solution was extracted with 3×200 mL of DCM and the combinedorganic layers were dried over anhydrous Na₂SO₄ concentrated undervacuum. The residue was applied onto a silica gel column and eluted witha gradient of ethyl acetate/petroleum ether (1:10 to 1:3). This resultedin 5 g (50%) of the title compound as a light yellow solid. MS-ESI:347.2 (M+1).

TABLE 4 The Intermediates in the following Table were prepared usingsimilar procedure as shown in Scheme 9 above for converting compound 27to Intermediate 11 starting from the appropriate materials. ExactIntermediate # Structure IUPAC Name Mass[M + H]⁺ Intermediate 12

N′-(tert-butyldimethylsilyl)-4-(2- hydroxypropan-2-yl)-2-methylbenzenesulfonimidamide 343.2 Intermediate 13

N′-(tert-butyldimethylsilyl)-3-(2- hydroxypropan-2-yl)benzenesulfonimidamide 329.1 Intermediate 14

N′-(tert-butyldimethylsilyl)-4-(2- hydroxypropan-2-yl)-3-methylbenzenesulfonimidamide 343.2 Intermediate 15

N′-(tert-butyldimethylsilyl)-4- fluoro-3-(2-hydroxypropan-2-yl)benzenesulfonimidamide 347.2 Intermediate 16

N′-(tert-butyldimethylsilyl)-3- fluoro-5-(2-hydroxypropan-2-yl)benzenesulfonimidamide 347.2 Intermediate 17

N′-(tert-butyldimethylsilyl)- 3-fluoro-4-(2-hydroxypropan-2-yl)benzenesulfonimidamide 347.2 Intermediate 18

N′-(tert-butyldimethylsilyl)- 2-chloro-4-(2-hydroxypropan-2-yl)benzenesulfonimidamide 363.1

TABLE 5 The Intermediate in the following Table was prepared usingsimilar procedure as shown in Scheme 9 above for converting compound 28to Intermediate 11 starting from methyl 4-(chlorosulfonyl)benzoate.Exact Intermediate # Structure IUPAC Name Mass[M + H]⁺ Intermediate 19

N′-(tert-butyldimethylsilyl)-4- (2-hydroxypropan-2-yl)benzenesulfonimidamide 329.2

N′-(tert-butyldimethylsilyl)-1-isopropyl-1H-pyrazole-3-sulfonimidamideStep 1: 1-Isopropyl-3-nitro-1H-pyrazole

Into a 250-mL round-bottom flask was placed a solution of3-nitro-1H-pyrazole (10 g, 88.4 mmol) in DMF (100 mL). This was followedby the addition of NaH (60% wt., 3.9 g, 97.5 mmol) in portions at 0° C.The resulting solution was stirred for 0.5 h at 0° C. This was followedby the addition of 2-bromopropane (14.1 g, 114.6 mmol) dropwise withstirring at 0° C. in 10 min. The resulting solution was stirred for 16 hat RT and then was quenched by the addition of 100 mL of water. Theresulting solution was extracted with 3×100 mL of ethyl acetate. Theorganic layers were combined and dried over anhydrous Na₂SO₄, thenconcentrated under vacuum. The residue was applied onto a silica gelcolumn and eluted with a gradient of ethyl acetate/petroleum ether (1:5to 1:3). This resulted in 11.8 g (86%) of the title compound as yellowoil. MS-ESI: 156.1 (M+1).

Step 2: 3-Amino-1-(propan-2-yl)-1H-pyrazole

Into a 250-mL round-bottom flask was placed a solution of1-isopropyl-3-nitro-1H-pyrazole (10.8 g, 69.6 mmol) in MeOH (100 mL).Then Pd/C (10% wt., 1.5 g) was added. The flask was evacuated andflushed three times with hydrogen. The mixture was stirred for 24 h atRT under an atmosphere of hydrogen. The solids were filtered out. Theresulting filtrate was concentrated under vacuum. This resulted in 7.27g (83%) of the title compound as yellow oil. MS-ESI: 126.1 (M+1).

Steps 3-4 used similar procedures for converting compound 27 to compound29 shown in Scheme 9 to afford compound 50 from compound 48. MS-ESI:188.0 (M−1).

Steps 5-6 were using the similar procedures for converting compound 30to Intermediate 11 shown in Scheme 9 to afford Intermediate 18 fromcompound 50. MS-ESI: 303.2 (M+1).

TABLE 6 The Intermediate in the following Table was prepared usingsimilar procedure as shown in Scheme 10 above for converting compound 48to Intermediate 18 starting from the appropriate materials. ExactIntermediate # Structure IUPAC Name Mass[M + H]⁺ Intermediate 21

N′-(tert-butyldimethylsilyl)-4- (methylsulfonyl) benzenesulfonimidamide349.1 Intermediate 22

N′-(tert-butyldimethylsilyl)-3- (methylsulfonyl) benzenesulfonimidamide349.1

N′-(tert-butyldimethylsilyl)-4-((dimethylamino)methyl)benzenesulfonimidamideStep 1: 4-Nitrobenzoyl Chloride

Into a 500-mL round-bottom flask was placed 4-nitrobenzoic acid (20 g,120 mmol), DCM (200 mL), and DMF (0.2 mL). This was followed by theaddition of oxalyl chloride (15 mL, 177.1 mmol) dropwise with stirringat 0° C. The resulting solution was stirred for 4 h at RT and then wasconcentrated under vacuum. This resulted in 22 g (crude) of the titlecompound as yellow oil. The crude product was used in the next step.

Step 2: N,N-dimethyl-4-nitrobenzamide

Into a 500-mL round-bottom flask was placed dimethylamine hydrochloride(6.5 g, 79.7 mmol), DCM (200 mL), and TEA (50 mL). This was followed bythe addition of 4-nitrobenzoyl chloride (22 g, 119 mmol) dropwise withstirring at 0° C. The resulting solution was stirred for 6 h at RT andthen was concentrated under vacuum. The resulting mixture was washedwith 2×50 mL of water. The solids were collected by filtration. Thisresulted in 16 g (69% over two steps) of the title compound as a whitesolid. MS-ESI: 195.1 (M+1).

Step 3: 4-Amino-N,N-dimethylbenzamide

Into a 250-mL round-bottom flask was placedN,N-dimethyl-4-nitrobenzamide (16 g, 82.4 mmol), MeOH (100 mL). ThenPd/C (10% wt., 1 g) was added. The flask was evacuated and flushed threetimes with hydrogen. The resulting solution was stirred for 12 h at RTunder an atmosphere of hydrogen. The solids were filtered out. Theresulting filtrate was concentrated under vacuum. This resulted in 13 g(96%) of the title compound as a white solid. MS-ESI: 165.1 (M+1). Steps4-5 used similar procedures for converting compound 27 to compound 29shown in Scheme 9 to afford compound 43 from compound 41. MS-ESI: 229.1(M+1).

Step 6: 4-((Dimethylamino)methyl)benzenesulfonamide

Into a 100-mL round-bottom flask purged with and maintained undernitrogen was placed a solution of N,N-dimethyl-4-sulfamoylbenzamide (1.8g, 7.9 mmol) in THF (50 mL). This was followed by the addition of 9-BBN(5.8 g) in portions at 0° C. The resulting solution was stirred for 12 hat 70° C. and then was quenched by the addition of 20 mL of water/ice.The resulting solution was extracted with 3×100 mL of ethyl acetate andthe organic layers were combined. The resulting mixture was washed with200 mL of water and then the organic layer was concentrated undervacuum. The residue was applied onto a silica gel column and eluted witha gradient of DCM/MeOH (20:1 to 15:1). This resulted in 1 g (59%) of thetitle compound as a white solid. MS-ESI: 215.1 (M+1).

Steps 7-8 were using the similar procedures for converting compound 30to Intermediate 11 shown in Scheme 9 to afford Intermediate 23 fromcompound 44. MS-ESI: 328.2 (M+1).

N′-(tert-butyldimethylsilyl)-3-((dimethylamino)methyl)benzenesulfonimidamideStep 1: 3-amino-N,N-dimethylbenzamide

Into a 1000-mL round-bottom flask was placed dimethylamine as ahydrochloride salt (16.3 g, 200 mmol) in DCM (500 mL), DIEA (25.83 mg,200 mmol). To the above was added 3-aminobenzoic acid (13.7 g, 100mmol), HATU (57 g, 150 mmol). The resulting solution was stirred for 1 hat RT. The reaction was then quenched by the addition of 500 mL of NH₄Cl(aq.). The resulting solution was extracted with 3×500 ml of ethylacetate and the organic layers combined and dried over anhydrous sodiumsulfate and concentrated. The residue was applied onto a silica gelcolumn and eluted with a gradient of DCM/methanol (50:1 to 20:1). Thisresulted in 13.14 g (80%) of the title compound as a yellow solid.MS-ESI: 165.1 (M+1).

Steps 2-6 used the similar procedures for converting compound 41 toIntermediate 23 shown in Scheme 11 to afford Intermediate 24 fromcompound 47. MS-ESI: 328.2 (M+1).

N′-(tert-butyldimethylsilyl)-4-((dimethylamino)methyl)-2-fluorobenzenesulfonimidamideSteps 1-5 used similar procedures for converting compound 38 to compound43 shown in Scheme 11 to afford compound 57. MS-ESI: 247.0 (M+1).

Step 6: 4-((Dimethylamino)methyl)-2-fluorobenzenesulfonamide

Into a 1-L round-bottom flask was placed a solution of3-fluoro-N,N-dimethyl-4-sulfamoylbenzamide (19.3 g, 78.4 mmol) in THF(200 mL). This was followed by the addition of LiAlH₄ (8.8 g, 231.9mmol) in portions at 0° C. The resulting solution was stirred for 12 hat RT and then was quenched by the addition of 10 mL of water. Theresulting mixture was concentrated under vacuum. The residue was appliedonto a silica gel column and eluted with a gradient of ethylacetate/petroleum ether (6:1 to 8:1). This resulted in 7.0 g (38%) ofthe title compound as a white solid. MS-ESI: 233.1 (M+1).

Steps 7-8 used similar procedures for converting compound 44 toIntermediate 23 shown in Scheme 11 to afford Intermediate 25. MS-ESI:346.2 (M+1).

N′-(tert-butyldimethylsilyl)-4-(2-hydroxypropan-2-yl)thiazole-2-sulfonimidamide Step 1:(2-Bromothiazol-4-yl)methanol

Into a 500-mL round-bottom flask was placed a solution of ethyl2-bromothiazole-4-carboxylate (14 g, 59.3 mmol), EtOH (200 mL). This wasfollowed by the addition of NaBH₄ (2.3 g, 60.5 mmol) in portions at 0°C. The resulting solution was stirred for 3 h at RT and then wasquenched by the addition of 100 mL of water. The resulting solution wasextracted with 2×200 mL of DCM. The organic layers were combined, driedover anhydrous Na₂SO₄ and then concentrated under vacuum. This resultedin 10.0 g (87%) of the title compound as colorless oil. MS-ESI: 195.9,193.9 (M+1).

Step 2: 2-Bromothiazole-4-carbaldehyde

Into a 250-mL round-bottom flask was placed a solution of(2-bromothiazol-4-yl)methanol (10.0 g, 51.5 mmol) in DCM (100 mL). Tothe solution was added Dess-Martin reagent (24.0 g, 56.6 mmol). Theresulting solution was stirred for 2 h at RT and then was concentratedunder vacuum. The residue was applied onto a silica gel column andeluted with a gradient of ethyl acetate/petroleum ether (1:50 to 1:20).This resulted in 8.0 g (81%) of the title compound as yellow oil.MS-ESI: 193.9, 191.9 (M+1).

Step 3: 1-(2-Bromothiazol-4-yl)ethanol

Into a 250-mL 3-necked round-bottom flask purged with and maintainedunder nitrogen was placed a solution of 2-bromothiazole-4-carbaldehyde(8 g, 41.7 mmol) in THF (100 mL). This was followed by the addition ofMeMgBr (3 M in THF, 15 mL) dropwise with stirring at 0° C. The resultingsolution was stirred for 2 h at RT and then was quenched by the additionof 100 mL of NH₄Cl (sat.). The resulting solution was extracted with3×100 mL of DCM and the combined organic layers were concentrated undervacuum. The residue was applied onto a silica gel column and eluted witha gradient of ethyl acetate/petroleum ether (1:10 to 1:5). This resultedin 6.0 g (69%) of the title compound as brown oil. MS-ESI: 209.9, 207.9(M+1).

Step 4: 2-Bromo-4-(1-(tert-butyldiphenylsilyloxy)ethyl)thiazole

Into a 250-mL round-bottom flask was placed a solution of1-(2-bromothiazol-4-yl)ethanol (6.0 g, 28.8 mmol) and 1H-imidazole (4.0g, 58.8 mmol) in DMF (50 mL). To the solution was added TBDPSCl (8.7 g,31.6 mmol). The resulting solution was stirred for 12 h at RT and thenwas diluted with 100 mL of water. The resulting solution was extractedwith 3×100 mL of DCM and the combined organic layers were concentratedunder vacuum. The residue was applied onto a silica gel column andeluted with a gradient of ethyl acetate/petroleum ether (1:100 to 1:50).This resulted in 10.0 g (78%) of the title compound as light yellow oil.MS-ESI: 448.1, 446.1 (M+1).

Step 5: 4-(1-(Tert-butyldiphenylsilyloxy)ethyl)thiazole-2-sulfonylchloride

Into a 250-mL 3-necked round-bottom flask purged with and maintainedunder nitrogen was placed a solution of2-bromo-4-(1-(tert-butyldiphenylsilyloxy)ethyl)thiazole (10.0 g, 22.4mmol) in THF (100 mL). This was followed by the addition of n-BuLi (2.5M in THF, 11 mL) dropwise with stirring at −78° C. The resultingsolution was stirred for 30 min at −78° C. To the above SO₂ gas wasintroduced. The reaction was warmed to RT and stirred for 30 min andthen was concentrated under vacuum. The residue was dissolved in DCM(100 mL) and then NCS (3.6 g, 26.9 mmol) was added. The resultingsolution was stirred for 30 min at RT and then was concentrated undervacuum. This resulted in 8.0 g (crude, 77%) of the title compound as awhite solid. The crude product was used in the next step.

Step 6:N-tert-butyl-4-(1-(tert-butyldiphenylsilyloxy)ethyl)thiazole-2-sulfonamide

Into a 100-mL round-bottom flask purged with and maintained undernitrogen was placed a solution of4-(1-(tert-butyldiphenylsilyloxy)ethyl)thiazole-2-sulfonyl chloride (8.0g, 17.2 mmol) in DCM (50 mL). To the solution were added TEA (3.5 g,34.6 mmol) and 2-methylpropan-2-amine (1.9 g, 26.0 mmol). The resultingsolution was stirred for 2 h at RT and then was concentrated undervacuum. The residue was applied onto a silica gel column and eluted witha gradient of ethyl acetate/petroleum ether (1:15 to 1:5). This resultedin 8.0 g (71%, 2 steps) of the title compound as brown oil. MS-ESI:503.2 (M+1).

Step 7: N-tert-butyl-4-(1-hydroxyethyl)thiazole-2-sulfonamide

Into a 250-mL round-bottom flask was placed a solution ofN-tert-butyl-4-(1-(tert-butyldiphenylsilyloxy)ethyl)thiazole-2-sulfonamide(8.0 g, 15.9 mmol) in THF (100 mL). To the solution was added TBAF (9.6g, 292.5 mmol). The resulting solution was stirred for 2 h at RT andthen was diluted with 100 mL of water. The resulting solution wasextracted with 3×100 mL of DCM and the combined organic layers wereconcentrated under vacuum. The residue was applied onto a silica gelcolumn and eluted with a gradient of ethyl acetate/petroleum ether (1:10to 1:3). This resulted in 4.0 g (95%) of the title compound as lightyellow oil. MS-ESI: 265.1 (M+1).

Step 8: 4-Acetyl-N-tert-butylthiazole-2-sulfonamide

Into a 100-mL round-bottom flask was placed a solution ofN-tert-butyl-4-(1-hydroxyethyl)thiazole-2-sulfonamide (4.0 g, 15.1 mmol)in DCM (50 mL). To the solution was added Dess-Martin reagent (7.1 g,16.6 mmol). The resulting solution was stirred for 2 h at RT and thenwas concentrated under vacuum. The residue was applied onto a silica gelcolumn and eluted with a gradient of ethyl acetate/petroleum ether (1:10to 1:3). This resulted in 3.5 g (88%) of the title compound as lightyellow oil. MS-ESI: 363.0 (M+1).

Step 9: 4-Acetylthiazole-2-sulfonamide

Into a 100-mL round-bottom flask was placed a solution of4-acetyl-N-tert-butylthiazole-2-sulfonamide (3.5 g, 13.3 mmol) in DCM (5mL). To the solution was added TFA (20 mL). The resulting solution wasstirred for 14 h at 40° C. and then was concentrated under vacuum. Theresidue was applied onto a silica gel column and eluted with a gradientof ethyl acetate/petroleum ether (1:10 to 1:3). This resulted in 2.5 g(91%) of the title compound as a gray solid. MS-ESI: 207.0 (M+1).

Steps 10-12 used similar procedures for converting compound 29 toIntermediate 11 shown in Scheme 9 to afford Intermediate 26 fromcompound 69. MS-ESI: 336.1 (M+1).

N′-(tert-butyldimethylsilyl)-2-(2-hydroxypropan-2-yl)thiazole-5-sulfonimidamideStep 1: 1-(Thiazol-2-yl)ethanol

Into a 500-mL round-bottom flask was placed 1-(thiazol-2-yl)ethanone (20g, 157 mmol), EtOH (200 mL). This was followed by the addition of NaBH₄(3 g, 81.3 mmol) in portions at 0° C. The resulting solution was stirredfor 2 h at RT and then was quenched by the addition of 10 mL of NH₄Cl(sat.). The resulting solution was diluted with 200 mL of water andextracted with 2×200 mL of DCM. The organic layers were combined anddried over anhydrous Na₂SO₄, then concentrated under vacuum. Thisresulted in 20 g (98%) of the title compound as light yellow oil.MS-ESI: 130.0 (M+1).

Step 2: 2-(1-(Tert-butyldiphenylsilyloxy)ethyl)thiazole

Into a 500-mL round-bottom flask was placed 1-(thiazol-2-yl)ethanol (20g, 154.8 mmol), DMF (150 mL), 1H-imidazole (20.5 g, 301 mmol). This wasfollowed by the addition of TBDPSCl (46 g, 167 mmol) dropwise withstirring at 0° C. The resulting solution was stirred for 2 h at RT andthen was diluted with 300 mL of water. The resulting solution wasextracted with 3×200 mL of DCM. The organic layers were combined andconcentrated under vacuum. The residue was applied onto a silica gelcolumn and eluted with a gradient of ethyl acetate/petroleum ether(1:100 to 1:80). This resulted in 55 g (97%) of the title compound ascolorless oil. MS-ESI: 368.1 (M+1).

Step 3: 2-(1-(Tert-butyldiphenylsilyloxy)ethyl)thiazole-5-sulfonylchloride

Into a 500-mL 3-necked round-bottom flask purged with and maintainedunder nitrogen was placed a solution of2-(1-(tert-butyldiphenylsilyloxy)ethyl)thiazole (30 g, 81.6 mmol) in THF(200 mL). This was followed by the addition of n-BuLi (2.5 M in THF,35.2 mL) dropwise with stirring at −78° C. The resulting solution wasstirred for 0.5 h at −78° C. and then SO₂ was introduced into the abovereaction mixture. The reaction was slowly warmed to RT and then NCS(12.8 g, 95.86 mmol) was added. The resulting solution was stirred for 1h at RT. The solids were filtered out. The resulting filtrate wasconcentrated under vacuum. This resulted in 30 g (crude, 79%) of thetitle compound as brown oil. The crude product was used in the nextstep.

Step 4:N-tert-butyl-2-(1-(tert-butyldiphenylsilyloxy)ethyl)thiazole-5-sulfonamide

Into a 500-mL round-bottom flask was placed2-(1-(tert-butyldiphenylsilyloxy)ethyl)thiazole-5-sulfonyl chloride(crude, 30 g, 64.37 mmol), DCM (200 mL), TEA (13 g, 128.47 mmol). Thiswas followed by the addition of 2-methylpropan-2-amine (5.6 g, 76.6mmol) dropwise with stirring at 0° C. The resulting solution was stirredfor 2 h at RT and then was concentrated under vacuum. The residue wasapplied onto a silica gel column and eluted with a gradient of ethylacetate/petroleum ether (1:30 to 1:20). This resulted in 25 g (61% overtwo steps) of the title compound as brown oil. MS-ESI: 503.2 (M+1).

Step 5: N-tert-butyl-2-(1-hydroxyethyl)thiazole-5-sulfonamide

Into a 500-mL round-bottom flask was placedN-tert-butyl-2-(1-(tert-butyldiphenylsilyloxy)ethyl)thiazole-5-sulfonamide(25 g, 49.7 mmol), THF (200 mL), TBAF (30 g, 99.67 mmol). The resultingsolution was stirred for 2 h at RT and then was diluted with 200 mL ofwater. The resulting solution was extracted with 3×200 mL of DCM. Theorganic layers were combined and concentrated under vacuum. The residuewas applied onto a silica gel column and eluted with a gradient of ethylacetate/petroleum ether (1:20 to 1:10). This resulted in 12 g (91%) ofthe title compound as light yellow oil. MS-ESI: 265.1 (M+1).

Step 6: 2-Acetyl-N-tert-butylthiazole-5-sulfonamide

Into a 500-mL round-bottom flask was placedN-tert-butyl-2-(1-hydroxyethyl)thiazole-5-sulfonamide (12 g, 45.4 mmol),DCM (200 mL). To this solution was added Dess-Martin reagent (20 g, 47.2mmol) in portions at RT. The resulting solution was stirred for 2 h atRT and then was concentrated under vacuum. The residue was applied ontoa silica gel column and eluted with a gradient of ethylacetate/petroleum ether (1:20 to 1:10). This resulted in 9 g (76%) ofthe title compound as a light yellow solid. MS-ESI: 263.0 (M+1).

Step 7: 2-Acetylthiazole-5-sulfonamide

Into a 100-mL round-bottom flask was placed2-acetyl-N-tert-butylthiazole-5-sulfonamide (7 g, 26.7 mmol), TFA (20mL). The resulting solution was stirred for 14 h at 70° C. and then wasconcentrated under vacuum. The residue was applied onto a silica gelcolumn and eluted with a gradient of ethyl acetate/petroleum ether (1:5to 1:3). This resulted in 5 g (91%) of the title compound as a yellowsolid. MS-ESI: 207.0 (M+1).

Step 8: 2-(2-Hydroxypropan-2-yl)thiazole-5-sulfonamide

Into a 500-mL 3-necked round-bottom flask purged with and maintainedunder nitrogen was placed 2-acetylthiazole-5-sulfonamide (5 g, 24.3mmol), THF (100 mL). This was followed by the addition of MeMgBr (3 M inTHF, 8.1 mL, 24.3 mmol) dropwise with stirring at 0° C. The resultingsolution was stirred for 14 h at RT and then was quenched by theaddition of 100 mL of NH₄Cl (sat.). The resulting solution was extractedwith 2×150 mL of DCM. The organic layers were combined and concentratedunder vacuum. The residue was applied onto a silica gel column andeluted with a gradient of ethyl acetate/petroleum ether (1:5 to 1:3).This resulted in 2.9 g (54%) of the title compound as a light yellowsolid. MS-ESI: 223.0 (M+1).

Steps 9-10 used similar procedures for converting compound 14 toIntermediate 1 shown in Scheme 6 to afford Intermediate 27 from compound80. MS-ESI: 336.1 (M+1).

N′-(tert-butyldimethylsilyl)-2-(2-hydroxypropan-2-yl)thiazole-5-sulfonimidamide Step 1:2-(2-Methyl-1,3-dioxolan-2-yl)thiazole

Into a 500-mL round-bottom flask was placed a solution of1-(thiazol-2-yl)ethanone (20 g, 157.0 mmol) in toluene (300 mL) andethane-1,2-diol (19.5 g, 314 mmol). To the solution was added TsOH (2.7g, 15.7 mmol). The resulting solution was refluxed overnight and waterwas separated from the solution during the reflux. The resultingsolution was diluted with 200 mL of water and extracted with 2×100 mL ofethyl acetate. The organic layers were combined, dried over anhydrousNa₂SO₄, and then concentrated under vacuum. This resulted in 26.6 g(99%) of the title compound as light yellow oil. MS-ESI: 172.0 (M+1).

Step 2: 2-(2-Methyl-1,3-dioxolan-2-yl)thiazole-5-sulfonamide

Into a 500-mL 3-necked round-bottom flask purged with and maintainedunder nitrogen was placed a solution of2-(2-methyl-1,3-dioxolan-2-yl)thiazole (14 g, 81.6 mmol) in THF (200mL). This was followed by the addition of n-BuLi (2.5 M in THF, 35.2 mL,88.0 mmol) dropwise with stirring at −78° C. The resulting solution wasstirred for 0.5 h at −78° C. and then SO₂ was introduced into the abovereaction mixture. The reaction was slowly warmed to RT and then NCS(12.8 g, 95.86 mmol) was added. The resulting solution was stirred for 1h at RT. The solids were filtered out. The resulting filtrate wasconcentrated under vacuum and then was diluted in DCM (160 mL). To theabove was added a saturated solution of ammonia in DCM (300 mL). Theresulting solution was stirred for 3 h at RT and then was concentratedunder vacuum. The residue was applied onto a silica gel column andeluted with a gradient of ethyl acetate/petroleum ether (1:20 to 1:5).This resulted in 12.5 g (61%) of the title compound as a yellow solid.MS-ESI: 251.0 (M+1).

Step 3: 2-Acetylthiazole-5-sulfonamide

Into a 250-mL round-bottom flask was placed a solution of2-(2-methyl-1,3-dioxolan-2-yl)thiazole-5-sulfonamide (12.5 g, 50.0 mmol)in THF (125 mL). To the above was added aq. HCl (4 N, 50.0 mL). Theresulting solution was stirred for 6 h at 70° C. The resulting solutionwas diluted with 100 mL of water and extracted with 2×200 mL of ethylacetate. The organic layers were combined, dried over anhydrous Na₂SO₄,then concentrated under vacuum. The residue was applied onto a silicagel column and eluted with a gradient of ethyl acetate/petroleum ether(1:2 to 1:1). This resulted in 9.3 g (90%) of the title compound as ayellow solid. MS-ESI: 207.0 (M+1). Steps 4-6 used the same proceduresfor converting compound 19 to Intermediate 2 shown in Scheme 7B toafford Intermediate 27 from compound 84. MS-ESI: 336.1 (M+1).

N′-(tert-butoxycarbonyl)-2-(2-hydroxypropan-2-yl)thiazole-5-sulfonimidamideStep 1: 2-(Thiazol-2-yl)propan-2-ol

Into a 10-L 4-necked round-bottom flask purged with and maintained undernitrogen was placed a solution of 1-(thiazol-2-yl)ethanone (200 g, 1.6mol) in THF (4 L). This was followed by the addition of MeMgBr (3 M inTHF, 942 mL) dropwise with stirring at 0° C. The mixture was stirred at0° C. for 2 h. After warmed the mixture to RT, the solution was stirredfor an additional 16 h. Then the reaction was quenched by the additionof 3 L of NH₄Cl (sat.). The resulting solution was extracted with 3×1 Lof ethyl acetate. The organic layers were combined, dried over anhydrousNa₂SO₄, then concentrated under vacuum. The residue was applied onto asilica gel column and eluted with a gradient of ethyl acetate/petroleumether (1:3 to 1:1). This resulted in 210 g (93%) of the title compoundas a brown oil. MS-ESI: 144.0 (M+1).

Step 2: Lithium 2-(2-hydroxypropan-2-yl)thiazole-5-sulfinate

Into a 10-L 4-necked round-bottom flask purged with and maintained undernitrogen was placed a solution of 2-(thiazol-2-yl)propan-2-ol (50 g,349.0 mmol) in THF (1.5 L). This was followed by the addition of n-BuLi(2.5 M in hexane, 350 mL) dropwise with stirring at −78° C. The mixturewas stirred at −78° C. for 1 h. Then SO₂ was bubbled into the mixturefor 15 min below −30° C. The mixture was stirred for an additional 1 hat RT and then was concentrated under vacuum. This resulted in 87 g(crude) of the title compound as a light yellow solid. The crude productwas used directly in the next step.

Step 3: Methyl 2-(2-hydroxypropan-2-yl)thiazole-5-sulfinate

Into a 2-L 3-necked round-bottom flask, lithium2-(2-hydroxypropan-2-yl)thiazole-5-sulfinate (87 g, crude) was dissolvedin anhydrous MeOH (500 mL). Then SOCl₂ (43 g, 360 mmol) was added to themixture dropwise with stirring at 0° C. The mixture was stirredovernight at RT and then was concentrated under vacuum. The residue wasdiluted with 500 mL of ethyl acetate. The resulting solution was washedwith 2×200 mL of water and 2×200 mL of brine. The solution was driedover anhydrous Na₂SO₄, then concentrated under vacuum. This resulted in72 g (crude) of the title compound as light yellow oil. The crudeproduct was used directly in the next step.

Step 4: 2-(2-Hydroxypropan-2-yl)thiazole-5-sulfinamide

Into a 10-L 4-necked round-bottom flask purged with and maintained undernitrogen was placed a solution of methyl2-(2-hydroxypropan-2-yl)thiazole-5-sulfinate (72 g, 326 mmol) in THF(500 mL). Then to the above NH₃ (0.5 M in THF, 2.0 L) was added. Aftercooling to −78° C., LiHMDS (1 M in THF, 2.0 L) was added to the mixturedropwise with stirring. Then the mixture was stirred at −78° C. for 2 h.The reaction was quenched by the addition of 500 mL of NH₄Cl (sat.). Theresulting solution was extracted with 3×300 mL of ethyl acetate. Theorganic layers were combined, dried over anhydrous Na₂SO₄, thenconcentrated under vacuum. This resulted in 32 g

-   -   (crude) of the title compound as brown oil. The crude product        was used directly in the next step.

Step 5: Tert-butyl 2-(2-hydroxypropan-2-yl)thiazol-5-ylsulfinylcarbamate

Into a 1-L 3-necked round-bottom flask purged with and maintained undernitrogen was placed a solution of2-(2-hydroxypropan-2-yl)thiazole-5-sulfinamide (32 g, crude) in THF (300mL). This was followed by the addition of LDA (2 M in THF, 116 mL)dropwise with string at 0° C. The mixture was stirred at 0° C. for 1 h,then (Boc)₂O (33.8 g, 155 mmol) was added in portions at 0° C. Themixture was warmed to RT and stirred for an additional 2 h. The reactionwas quenched with 200 mL of ice-water (200 mL), and the pH value of thesolution was adjusted to 6 with HCOOH. The resulting solution wasextracted with 3×200 mL of ethyl acetate. The organic layers werecombined, dried over anhydrous Na₂SO₄, then concentrated under vacuum.The residue was applied onto a silica gel column and eluted with agradient of ethyl acetate/petroleum ether (1:2 to 1:1). This resulted in19 g (18%, 4 steps) of the title compound as a white solid.

Step 6:N-(tert-butyldimethylsilyl)-2-(2-hydroxypropan-2-yl)thiazole-5-sulfonimidamide

Into a 1-L 3-necked round-bottom flask purged with and maintained undernitrogen, tert-butyl2-(2-hydroxypropan-2-yl)thiazol-5-ylsulfinylcarbamate (19 g, 62 mmol)was dissolved in fresh distilled ACN (200 mL). Then to the abovesolution was added NCS (9.8 g, 74 mmol) in portions. The mixture wasstirred for 1 h at RT and then NH₃ was bubbled in the mixture for 15min. The mixture was stirred at RT for 2 h and then was concentratedunder vacuum. The residue was applied onto a silica gel column andeluted with a gradient of ethyl acetate/petroleum ether (1:2 to 1:1).This resulted in 13 g (65%) of the title compound as a white solid.

4-(2-Hydroxypropan-2-yl)-N′-methylthiophene-2-sulfonimidamide

Step 1 used the procedures for converting compound 15 to Intermediate 1shown in Scheme 6 to afford compound 93 by substituting ammonia withmethylamine. MS-ESI: 349.1 (M+1).

Step 2: 4-(2-Hydroxypropan-2-yl)-N′-methylthiophene-2-sulfonimidamide

Into a 25-mL round-bottom flask purged with under nitrogen was placed asolution ofN′-(tert-butyldimethylsilyl)-4-(2-hydroxypropan-2-yl)-N-methylthiophene-2-sulfonimidamide(500 mg, 1.43 mmol) in DCM (10 mL). To the solution was added HF/Py (70%wt., 200 mg). The resulting solution was stirred for 2 h at RT. The pHvalue of the solution was adjusted to 8 with aq. Na₂CO₃ (5% wt.). Theresulting solution was extracted with 3×10 mL of ethyl acetate. Theorganic layers were combined, dried over anhydrous Na₂SO₄, thenconcentrated under vacuum. This resulted in 300 mg (89%) of the titlecompound as brown oil. MS-ESI: 235.0 (M+1).

Schemes for the Preparation of Isocyanate Intermediates 30-58

Schemes below illustrate the synthesis of isocyanates.

4-Fluoro-2,6-diisopropylbenzenamine Step 1:4-Fluoro-2,6-bis(prop-1-en-2-yl)aniline

Into a 500-mL round-bottom flask purged with and maintained undernitrogen was placed 2,6-dibromo-4-fluoroaniline (15 g, 55.8 mmol),dioxane (150 mL), water (15 mL), Cs₂CO₃ (55 g, 169 mmol),4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (25 g, 149mmol), and Pd(dppf)C₁₂ (4 g, 5.47 mmol). The resulting solution wasstirred for 15 h at 100° C. and then was concentrated under vacuum. Theresidue was applied onto a silica gel column and eluted with a gradientof ethyl acetate/petroleum ether (1:10 to 1:8). This resulted in 9.2 g(86%) of the title compound as brown oil. MS-ESI: 192.1 (M+1).

Step 2: 4-Fluoro-2,6-bis(propan-2-yl)aniline

Into a 500-mL round-bottom flask was placed4-fluoro-2,6-bis(prop-1-en-2-yl)aniline (9.2 g, 48.1 mmol), and MeOH(200 mL). Then Pd/C (10% wt., 900 mg) was added. The flask was evacuatedand flushed three times with hydrogen. The resulting solution wasstirred for 12 h at RT under an atmosphere of hydrogen. The solids werefiltered out. The resulting filtrate was concentrated under vacuum. Theresidue was applied onto a silica gel column and eluted with a gradientof ethyl acetate/petroleum ether (1:10 to 1:8). This resulted in 7.2 g(77%) of the title compound as brown oil. MS-ESI: 196.1 (M+1).

4-Amino-2-fluoro-3,5-diisopropylbenzonitrile Step 1:4-Amino-3,5-dibromo-2-fluorobenzonitrile

Into a 1-L round-bottom flask was placed 4-amino-2-fluorobenzonitrile(25 g, 184 mmol), ACN (500 mL), and NBS (81.7 g, 459 mmol). Theresulting solution was stirred overnight at 75° C. and then wasconcentrated under vacuum. The residue was applied onto a silica gelcolumn and eluted with a gradient of ethyl acetate/petroleum ether(1:100 to 1:98). This resulted in 50 g (93%) of the title compound asbrown oil. MS-ESI: 294.9/292.9/296.9 (M+1).

Steps 2-3 used similar procedures for converting compound 94 toIntermediate 30 shown in Scheme 18 to afford Intermediate 31 fromcompound 97. MS-ESI: 221.1 (M+1).

4-(Difluoromethoxy)-2,6-diisopropylbenzenamine Step 1:2,6-Dibromo-4-(difluoromethoxy)benzenamine

Into a 100-mL round-bottom flask was placed4-(difluoromethoxy)benzenamine (3 g, 18.9 mmol), ACN (30 mL), and NBS(7.7 g, 43.3 mmol). The resulting solution was stirred overnight at RTand then was concentrated under vacuum. The residue was applied onto asilica gel column and eluted with a gradient of ethyl acetate/petroleumether (1:30 to 1:20). This resulted in 2.9 g (48%) of the title compoundas brown oil. MS-ESI: 317.9/315.9/319.9 (M+1).

Steps 2-3 used similar procedures for converting compound 94 toIntermediate 30 shown in Scheme 18 to afford Intermediate 32 fromcompound 100″. MS-ESI: 244.1 (M+1).

4-(Difluoromethoxy)-2-ethyl-6-isopropylbenzenamine Step 1:2-Bromo-4-(difluoromethoxy)benzenamine

Into a 250-mL round-bottom flask purged with and maintained undernitrogen was placed 4-(difluoromethoxy)benzenamine (10 g, 62.8 mmol),ACN (100 mL), and NBS (5.59 g, 31.4 mmol). The resulting solution wasstirred for 1 h RT and then was concentrated under vacuum. The residuewas applied onto a silica gel column and eluted with a gradient of ethylacetate/petroleum ether (1:20 to 1:10). This resulted in 7.9 g (53%) ofthe title compound as red oil. MS-ESI: 238.0/240.0 (M+1).

Step 2: 4-(Difluoromethoxy)-2-(prop-1-en-2-yl)benzenamine

Into a 250-mL round-bottom flask purged with and maintained undernitrogen was placed 2-bromo-4-(difluoromethoxy)benzenamine (7.9 g, 33.2mmol), dioxane (100 mL), water (10 mL), Cs₂CO₃ (32.46 g, 99.63 mmol),4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (8.36 g, 49.8mmol), and Pd(dppf)C₁₂ (1.21 g, 1.65 mmol). The resulting solution wasstirred overnight at 90° C. The solids were filtered out. The filtratewas concentrated under vacuum. The residue was applied onto a silica gelcolumn and eluted with a gradient of ethyl acetate/petroleum ether (1:30to 1:20). This resulted in 5.3 g (80%) of the title compound as a yellowsolid. MS-ESI: 200.1 (M+1).

Step 3: 4-(Difluoromethoxy)-2-isopropylbenzenamine

Into a 250-mL round-bottom flask was placed4-(difluoromethoxy)-2-(prop-1-en-2-yl)benzenamine (5.3 g, 26.6 mmol) inMeOH (100 mL). Then Pd/C (10% wt., 500 mg) was added.

The flask was evacuated and filled three times with hydrogen. Theresulting solution was stirred for 3 h at RT under hydrogen. The solidswere filtered out. The resulting filtrate was concentrated under vacuum.This resulted in 5.15 g (96%) of the title compound as red oil. MS-ESI:202.1 (M+1).

Step 4: 2-Bromo-4-(difluoromethoxy)-6-isopropylbenzenamine

Into a 500-mL round-bottom flask was placed4-(difluoromethoxy)-2-isopropylbenzenamine (5.15 g, 25.6 mmol), CHCl₃(200 mL), Fe turnings (500 mg), and Bra (4.45 g, 27.9 mmol). Theresulting mixture was stirred overnight at 70° C. and then was quenchedby the addition of 200 mL of water. The resulting solution was extractedwith 3×100 mL of DCM and the organic layers combined and concentratedunder vacuum. The residue was applied onto a silica gel column andeluted with a gradient of ethyl acetate/petroleum ether (1:30 to 1:20).This resulted in 6.98 g (97%) of the title compound as dark red oil.MS-ESI: 280.0/282.0 (M+1).

Step 5: 4-(Difluoromethoxy)-2-isopropyl-6-vinylbenzenamine

Into a 250-mL round-bottom flask purged with and maintained undernitrogen was placed 2-bromo-4-(difluoromethoxy)-6-isopropylbenzenamine(3 g, 10.7 mmol), dioxane (100 mL), water (10 mL), Cs₂CO₃ (10.47 g,32.13 mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (2.47 g,16.0 mmol), and Pd(dppf)C₁₂ (784 mg, 1.07 mmol). The resulting solutionwas stirred overnight at 90° C. and then was concentrated under vacuum.The residue was applied onto a silica gel column and eluted with agradient of ethyl acetate/petroleum ether (1:30 to 1:20). This resultedin 2.3 g (94%) of the title compound as dark green oil. MS-ESI: 228.1(M+1).

Step 6: 4-(Difluoromethoxy)-2-ethyl-6-isopropylbenzenamine

Into a 250-mL round-bottom flask was placed4-(difluoromethoxy)-2-isopropyl-6-vinylbenzenamine (2.3 g, 10.1 mmol),MeOH (100 mL). Then Pd/C (10% wt., 200 mg) was added. The flask wasevacuated and filled three times with hydrogen. The resulting solutionwas stirred overnight at RT under hydrogen. The solids were filteredout. The filtrate was concentrated under vacuum. This resulted in 2.2 g(95%) of the title compound as red oil. MS-ESI: 230.1 (M+1).

TABLE 7 The Intermediate 34 in the following Table was prepared fromcompound 105″ using similar procedure as shown in Scheme 21 above forconverting compound 105″ to 106″. Exact Intermediate # Structure IUPACName Mass[M + H]⁺ Intermediate 34

2-Cyclopropyl-4-(difluoromethoxy)- 6-isopropylbenzenamine 242.1

4-Amino-5-cyclopropyl-2-fluoro-3-isopropylbenzonitrile Step 1:4-Amino-5-bromo-2-fluorobenzonitrile

Into a 250-mL round-bottom flask was placed a solution of4-amino-2-fluorobenzonitrile (9 g, 66.1 mmol) in ACN (120 mL). Then NBS(12.4 g, 69.7 mmol) was added. The resulting solution was stirredovernight at 80° C. and then was concentrated under vacuum. The residuewas applied onto a silica gel column and eluted with a gradient of ethylacetate/petroleum ether (1:20 to 1:10). This resulted in 10.9 g (77%) ofthe title compound as a yellow solid. MS-ESI: 215.0/217.0 (M+1). ¹H NMR(300 MHz, DMSO-d6) δ 7.89 (d, J=6.0 Hz, 1H), 6.69 (br s, 2H), 6.63 (d,J=12.0 Hz, 1H).

Step 2: 4-Amino-5-cyclopropyl-2-fluorobenzonitrile

Into a 250-mL round-bottom flask purged with and maintained undernitrogen was placed a solution of 4-amino-5-bromo-2-fluorobenzonitrile(6.37 g, 29.6 mmol) in dioxane (70 mL) and water (10 mL). To thesolution were added Cs₂CO₃ (9.7 g, 29.8 mmol), cyclopropylboronic acid(3.8 g, 44.2 mmol) and Pd(dppf)C₁₂ (1.08 g, 1.48 mmol). The resultingsolution was stirred overnight at 90° C. and then was concentrated undervacuum. The residue was applied onto a silica gel column and eluted witha gradient of ethyl acetate/petroleum ether (1:10 to 1:5). This resultedin 5.03 g (96%) of the title compound as a yellow solid. MS-ESI: 177.1(M+1).

Step 3: 4-Amino-3-bromo-5-cyclopropyl-2-fluorobenzonitrile

Into a 250-mL round-bottom flask was placed a solution of4-amino-5-cyclopropyl-2-fluorobenzonitrile (5.03 g, 28.7 mmol) in ACN(50 mL). To the solution was added NBS (5.6 g, 31.5 mmol). The resultingsolution was stirred overnight at 80° C. and then was concentrated undervacuum. The residue was applied onto a silica gel column and eluted witha gradient of ethyl acetate/petroleum ether (1:10 to 1:5). This resultedin 6.972 g (96%) of the title compound as a yellow solid. MS-ESI:255.0/257.0 (M+1).

Step 4: 4-Amino-5-cyclopropyl-2-fluoro-3-(prop-1-en-2-yl)benzonitrile

Into a 250-mL round-bottom flask purged with and maintained undernitrogen was placed a solution of4-amino-3-bromo-5-cyclopropyl-2-fluorobenzonitrile (6.972 g, 27.33 mmol)in dioxane (120 mL) and water (20 mL). To the solution were added4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (6.9 g, 41.00mmol), Cs₂CO₃ (13.4 g, 41.00 mmol) and Pd(dppf)C₁₂ (0.4 g, 0.55 mmol).The resulting solution was stirred overnight at 80° C. and then wasconcentrated under vacuum. The residue was applied onto a silica gelcolumn and eluted with a gradient of ethyl acetate/petroleum ether (1:10to 1:5). This resulted in 4.73 g (80%) of the title compound as a yellowsolid. MS-ESI: 217.1 (M+1).

Step 5: 4-Amino-5-cyclopropyl-2-fluoro-3-isopropylbenzonitrile

Into a 250-mL round-bottom flask was placed a solution of4-amino-5-cyclopropyl-2-fluoro-3-(prop-1-en-2-yl)benzonitrile (4.73 g,21.97 mmol), MeOH (100 mL). To the solution was added AcOH (0.5 mL).Then Pd/C (10% wt., 500 mg) was added. The flask was evacuated andfilled three times with hydrogen. The resulting solution was stirred for4 h at 40° C. under an atmosphere of hydrogen. The solids were filteredout. The filtrate was concentrated under vacuum. This resulted in 4.71 g(99%) of the title compound as a light yellow solid. MS-ESI: 219.1(M+1).

8-Fluoro-1,2,3,5,6,7-hexahydro-s-indacen-4-amine Step 1:3-Chloro-1-(2,3-dihydro-1H-inden-5-yl)propan-1-one

Into a 3-L round-bottom flask was placed a solution of AlCl₃ (111 g, 834mmol) in DCM (1200 mL). This was followed by the addition of a solutionof 2,3-dihydro-1H-indene (90 g, 762 mmol) and 3-chloropropanoyl chloride(96.3 g, 759 mmol) in DCM (300 mL) dropwise with stirring at −10° C. in30 min. The resulting solution was stirred for 16 h at RT. Then thereaction mixture was added dropwise to cold HCl (3 N, 1200 mL) over 45min at −10° C. The resulting solution was extracted with 3×600 mL of DCMand the organic layers were combined, dried over anhydrous Na₂SO₄, thenconcentrated under vacuum. This resulted in 160.5 g (crude) of the titlecompound as a yellow solid. The crude product was used in the next step.

Step 2: 1,2,3,5,6,7-Hexahydro-s-indacen-1-one

Into a 1-L round-bottom flask was placed a solution of3-chloro-1-(2,3-dihydro-1H-inden-5-yl)propan-1-one (160.5 g, 759 mmol)in conc. H₂SO₄ (900 mL). The resulting solution was stirred for 16 h at55° C. and then was quenched by adding the reaction mixture carefully to4500 mL of water/ice. The solids were collected by filtration and driedover infrared lamp for 24 h. The crude mixture was purified bychromatography and eluted with ethyl acetate/petroleum ether (1:100).This resulted in 10 g (7.6%) of 1,6,7,8-tetrahydro-as-indacen-3(2H)-one(compound 113″a) and 112.2 g (85%) of the title compound (compound 113″)as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 7.44 (s, 1H), 7.39 (s,1H), 3.13-2.79 (m, 8H), 2.70-2.55 (m, 2H), 2.20-1.90 (m, 2H). ¹H NMR(400 MHz, DMSO-d₆) δ 7.49 (d, J=7.7 Hz, 1H), 7.31 (d, J=7.7 Hz, 1H),3.19-2.98 (m, 4H), 2.93-2.80 (m, 3H), 2.68-2.54 (m, 2H), 2.15-1.95 (m,2H).

Step 3: 4-nitro-2,3,6,7-tetrahydro-s-indacen-1(511)-one (114) (Major)and 8-nitro-2,3,6,7-tetrahydro-s-indacen-1(511)-one (115) (Minor)

Into a 1-L round-bottom flask was placed a solution of1,2,3,5,6,7-hexahydro-s-indacen-1-one (80 g, 464.5 mmol) in H₂SO₄ (500mL). Then HNO₃ (58.5 g, 929 mmol) was added dropwise over 1 h at 0° C.The resulting solution was stirred for 1 hr at 0° C. The reactionmixture was slowly added to a mixture of water/ice (1000 mL) and DCM(500 mL) with ice bath cooling. The organic layer was collected, driedover Na₂SO₄ and concentrated under vacuum. This resulted in 90 g (90%)of the mixture of 4-nitro-2,3,6,7-hexahydro-s-indacen-1-one and8-nitro-2,3,6,7-tetrahydro-s-indacen-1(5H)-one as a yellow solid.

Step 4: 1,2,3,5,6,7-hexahydro-s-indacen-4-amine

Into a 1-L round-bottom flask was placed a solution of the mixture of4-nitro-1,2,3,5,6,7-hexahydro-s-indacen-1-one and8-nitro-2,3,6,7-tetrahydro-s-indacen-1(5H)-one (21.7 g, 100 mmol) inMeOH (300 mL). To the solution was added MSA (11.5 g, 120 mmol). ThenPd(OH)₂/C (20% wt, 5.5 g) was added. The flask was evacuated and filledthree times with hydrogen. The resulting mixture was stirred for 16 h atRT under hydrogen (50 psi). The solids were filtered out and washed withmethanol. The methanol filtrate and wash was diluted with water (500 mL)and the pH was adjusted to 10.6 with 2N NaOH. The resulting slurry wasfiltered and the crude solids were recrystallized from methanol/water(9:1) with heating. This resulted in 13.7 g (79%) of the title compoundas an off-white solid.

Step 5: 8-Nitro-1,2,3,5,6,7-hexahydro-s-indacen-4-amine

Into a 500-mL round-bottom flask was placed1,2,3,5,6,7-hexahydro-s-indacen-4-amine (8 g, 46.2 mmol), EtOH (200 mL),and 2,3,5,6-tetrabromo-4-methyl-4-nitrocyclohexa-2,5-dienone (21.6 g,46.1 mmol). The resulting solution was stirred for 12 h at RT and thenwas concentrated under vacuum. The residue was applied onto a silica gelcolumn and eluted with a gradient of ethyl acetate/petroleum ether (1:50to 1:30). This resulted in 5 g (50%) of the title compound as a yellowsolid. MS-ESI: 219.1 (M+1).

Step 6: 4-Fluoro-8-nitro-1,2,3,5,6,7-hexahydro-s-indacene

Into a 100-mL round-bottom flask was placed8-nitro-1,2,3,5,6,7-hexahydro-s-indacen-4-amine (5 g, 22.9 mmol) andHF/Py (70% wt., 20 mL). This was followed by the addition of3-methylbutyl nitrite (3 g, 25.6 mmol) dropwise with stirring at 0° C.The resulting solution was stirred for 2 h at RT and then was dilutedwith 50 mL of water. The resulting solution was extracted with 3×50 mLof DCM. The organic layers were combined and dried over anhydrousNa₂SO₄, then concentrated under vacuum. This resulted in 4 g (crude,79%) of the title compound as brown oil.

Step 7: 8-Fluoro-1,2,3,5,6,7-hexahydro-s-indacen-4-amine

Into a 100-mL round-bottom flask was placed4-fluoro-8-nitro-1,2,3,5,6,7-hexahydro-s-indacene (4 g, 18.1 mmol) inMeOH (50 mL). Then Pd/C (10% wt., 0.5 g) was added. The flask wasevacuated and filled three times with hydrogen. The resulting mixturewas stirred for 12 h at RT under an atmosphere of hydrogen. The solidswere filtered out and the filtrate was concentrated under vacuum. Theresidue was applied onto a silica gel column and eluted with a gradientof ethyl acetate/petroleum ether (1:10 to 1:5). This resulted in 2 g(46%, 2 steps) of the title compound as a white solid. MS-ESI: 192.1(M+1).

Step 1: 4-nitro-2,3,6,7-tetrahydro-s-indacen-1(5H)-one

Into a 1-L round-bottom flask was placed a solution of1,2,3,5,6,7-hexahydro-s-indacen-1-one (40 g, 232 mmol) in H₂SO₄ (250mL). Then HNO₃ (29 g, 464 mmol) was added dropwise over 1 h at 0° C. Theresulting solution was stirred for 1 hr at 0° C. The reaction mixturewas slowly added to a mixture of water/ice (500 mL) and DCM (250 mL)with ice bath cooling. The organic layer was collected, dried overanhydrous Na₂SO₄ and concentrated under vacuum. The crude product waspurified by silica gel column with a gradient of ethyl acetate andpetroleum ether (1:50 to 1:1). This resulted in minor product 5 g (10%)of the title compound and major product 30 g (60%) of8-nitro-2,3,6,7-tetrahydro-s-indacen-1(5H)-one both as a yellow solid.

Step 2: 1-methylene-4-nitro-1,2,3,5,6,7-hexahydro-s-indacene

Into a 250-mL round-bottom flask was placed a solution ofmethyltriphenylphosphanium bromide (16.4 g, 46.04 mmol) and t-BuOK (5.2g, 46.0 mmol) in THF (150 mL) at 0° C. The resulting solution wasstirred for 30 min at 0° C. Then the solution of4-nitro-1,2,3,5,6,7-hexahydro-s-indacen-1-one (5 g, 23.0 mmol) in THF(10 mL) was added dropwise to the reaction mixture at 0° C. Theresulting solution was stirred overnight at RT. The resulting mixturewas concentrated. The residue was applied onto a silica gel column withethyl acetate/petroleum ether (1:10). This resulted in 2.6 g (52%) ofthe title compound as a green solid.

Step 3: 1-methyl-1,2,3,5,6,7-hexahydro-s-indacen-4-amine

Into a 100-mL round-bottom flask was placed a solution of1-methylidene-4-nitro-1,2,3,5,6,7-hexahydro-s-indacene (2.6 g, 12.1mmol) in MeOH (20 mL), Pd/C (10% wt, 300 mg) was added. The flask wasevacuated and filled three times with hydrogen, then H₂ (g) wasintroduced in with a balloon. The resulting solution was stirred for 2 hat RT. The Pd/C catalyst was filtered out. The filtrate wasconcentrated. This resulted in 2 g of the title compound as red oil.

TABLE 8 Intermediate 38 in the following Table was prepared fromCompound 114″ using similar procedure as shown in Scheme 24 above forconverting compound 115″ to intermediate 37. Exact Intermediate #Structure IUPAC Name Mass[M + H]⁺ Intermediate 38

3-methyl-1,2,3,5,6,7-hexahydro- s-indacen-4-amine 188.1

8-Chloro-1,2,3,5,6,7-hexahydro-s-indacen-4-amine Step 1:8-Chloro-1,2,3,5,6,7-hexahydro-s-indacen-4-amine

Into a 50-mL round-bottom flask was placed a solution of1,2,3,5,6,7-hexahydro-s-indacen-4-amine (1.73 g, 9.99 mmol) in DMF (10mL). To the solution was added NCS (1.47 g, 11.0 mmol). The resultingsolution was stirred overnight at RT and then was diluted with 30 mL ofDCM. The resulting mixture was washed with 3×10 mL of water and theorganic layer was concentrated under vacuum. The residue was appliedonto a silica gel column and eluted with a gradient of ethylacetate/petroleum ether (1:20 to 1:10). This resulted in 1.88 g (91%) ofthe title compound as a yellow solid. MS-ESI: 208.1/210.1 (M+1).

8-Amino-1,2,3,5,6,7-hexahydro-s-indacene-4-carbonitrile Step 1:8-Bromo-1,2,3,5,6,7-hexahydro-s-indacen-4-amine

Into a 100-mL round-bottom flask was placed a solution of1,2,3,5,6,7-hexahydro-s-indacen-4-amine (2.6 g, 15.0 mmol) in DMF (30mL). To the solution was added NBS (2.9 g, 16.3 mmol). The resultingsolution was stirred for 12 h at RT and then was diluted with 80 mL ofethyl acetate.

The resulting mixture was washed with 3×20 mL of water and concentratedunder vacuum. The residue was applied onto a silica gel column andeluted with a gradient of ethyl acetate/petroleum ether (1:30 to 1:20).This resulted in 3.0 g (79%) of the title compound as a brown solid.MS-ESI: 252.0, 254.0 (M+1).

Step 2: 8-Amino-1,2,3,5,6,7-hexahydro-s-indacene-4-carbonitrile

Into a 50-mL round-bottom flask purged with and maintained undernitrogen was placed a solution of8-bromo-1,2,3,5,6,7-hexahydro-s-indacen-4-amine (725 mg, 2.88 mmol) inDMF (10 mL). To the solution were added t-BuOK (330 mg, 2.90 mmol), CuCN(386 mg, 4.32 mmol), and Pd(dppf)C₁₂ (424 mg, 0.58 mmol). The resultingsolution was stirred for 12 h at 120° C. and then was diluted with 20 mLof water. The resulting solution was extracted with 3×20 mL ethylacetate. The organic layers were combined, dried over anhydrous Na₂SO₄,then concentrated under vacuum. The residue was applied onto a silicagel column and eluted with a gradient of ethyl acetate/petroleum ether(1:60 to 1:40). This resulted in 192 mg (34%) of the title compound as ayellow solid. MS-ESI: 199.1 (M+1).

4-Amino-3,5-diisopropylbenzonitrile Step 1:4-Amino-3,5-diisopropylbenzonitrile

Into a 100-mL round-bottom flask purged with and maintained undernitrogen was placed a solution of 4-bromo-2,6-diisopropylbenzenamine(5.1 g, 19.9 mmol) in DMF (30 mL). To the solution were added Zn(CN)₂(2.80 g, 23.9 mmol), Pd(dppf)C₁₂ (732 mg, 1.00 mmol) and t-BuOK (3.36 g,29.9 mmol). The resulting mixture was stirred for 16 h at 120° C. andthen was diluted with 30 mL of water. The solution was extracted with3×30 mL of ethyl acetate and the combined organic layers wereconcentrated under vacuum. The residue was applied onto a silica gelcolumn and eluted with a gradiente of ethyl acetate/petroleum ether(1:30 to 1:20). This resulted in 3.2 g (80%) of the title compound as ayellow solid. MS-ESI: 203.1 (M+1).

8-(Difluoromethoxy)-1,2,3,5,6,7-hexahydro-s-indacen-4-amine Step 1:1,2,3,5,6,7-Hexahydro-s-indacene

Into a 1-L round-bottom flask was placed a solution of1,2,3,5,6,7-hexahydro-s-indacen-1-one (37.2 g, 216 mmol) and MSA (42 g,437.5 mmol) in MeOH (300 mL). Then Pd(OH)₂/C (20% wt, 8 g) was added.The flask was evacuated and filled three times with hydrogen. Theresulting solution was stirred for 16 h at RT under an atmosphere ofhydrogen. The solids were filtered out. The resulting mixture wasconcentrated under vacuum. The residue was applied onto a silica gelcolumn and eluted with a gradient of ethyl acetate/petroleum ether(1:150 to 1:100). This resulted in 27.1 g (79%) of the title compound asa white solid.

Step 2: 4-Bromo-1,2,3,5,6,7-hexahydro-s-indacene

Into a 500-mL 3-necked round-bottom flask purged with and maintainedunder nitrogen was placed a solution of 1,2,3,5,6,7-hexahydro-s-indacene(15 g, 94.8 mmol) in CCl₄ (200 mL). Then 12 (1.2 g, 4.72 mmol) wasadded. This was followed by the addition of a solution of Bra (16 g, 100mmol) in CCl₄ (50 mL) dropwise with stirring at 0° C. in 10 min. Theresulting solution was stirred for 2 h at 0° C. The reaction was thenquenched by the addition of 150 mL of NH₄Cl (sat.). The resultingsolution was extracted with 3×150 mL of DCM and the combined organiclayers were dried over anhydrous Na₂SO₄ and concentrated under vacuum.The crude product was purified by silica gel column with a gradient ofethyl acetate/hexane (1:500 to 1:100). This resulted in 19 g (85%) ofthe title compound as yellow oil. ¹H NMR (300 MHz, DMSO-d₆) δ 7.02 (s,1H), 2.95-2.75 (m, 8H), 2.03-2.01 (m, 4H)

Step 3: 1,2,3,5,6,7-Hexahydro-s-indacen-4-ol

Into a 500-mL 3-necked round-bottom flask purged with and maintainedunder nitrogen was placed a solution of4-bromo-1,2,3,5,6,7-hexahydro-s-indacene (5 g, 21.08 mmol) in THF (150mL). This was followed by the addition of n-BuLi (2.5 M in hexane, 10mL) dropwise with stirring at −78° C. The resulting solution was stirredfor 30 min at −78° C. Then to the above was added trimethyl borate (2.6g, 25.30 mmol) dropwise with stirring at −78° C. The reaction was warmedto RT slowly and then was stirred for 1 h at RT. Then to the mixture wasadded AcOH (2.0 mL, 33.20 mmol) and H₂O₂ (1.0 mL, 28.88 mmol) dropwisewith stirring at RT. The resulting solution was stirred for 2 h at RTand then was quenched by the addition of 200 mL of NH₄Cl (sat.). Theresulting solution was extracted with 3×200 mL of DCM. The organiclayers were combined and dried over anhydrous Na₂SO₄, then concentratedunder vacuum. The residue was applied onto a silica gel column andeluted with a gradient of ethyl acetate/petroleum ether (1:7 to 1:5).This resulted in 1.9 g (52%) of the title compound as an off-whitesolid. MS-ESI: 175.1 (M+1).

Step 4: 8-Nitro-1,2,3,5,6,7-hexahydro-s-indacen-4-ol

Into a 250-mL round-bottom flask purged with and maintained undernitrogen was placed a solution of 1,2,3,5,6,7-hexahydro-s-indacen-4-ol(1.9 g, 10.9 mmol) in EtOH (100 mL). To the solution was added2,3,5,6-tetrabromo-4-methyl-4-nitrocyclohexa-2,5-dienone (6.1 g, 13.1mmol). The resulting solution was stirred overnight at RT and then wasconcentrated under vacuum. The residue was applied onto a silica gelcolumn and eluted with a gradient of ethyl acetate/petroleum ether (1:5to 1:3). This resulted in 1.1 g (46%) of the title compound as a lightyellow solid. MS-ESI: 218.1 (M−1).

Step 5: 4-(Difluoromethoxy)-8-nitro-1,2,3,5,6,7-hexahydro-s-indacene

Into a 100-mL round-bottom flask purged with and maintained undernitrogen was placed a solution of8-nitro-1,2,3,5,6,7-hexahydro-s-indacen-4-ol (1.1 g, 5.0 mmol) in DMF(20 mL) and water (2 mL). To the solution were added K2CO₃ (1.4 g, 10.0mmol) and sodium 2-chloro-2,2-difluoroacetate (1.5 g, 10.0 mmol). Theresulting solution was stirred for 1 h at 120° C. and then was dilutedwith 20 mL of water. The pH value of the solution was adjusted to 7 withaq. HCl (1 N). The resulting solution was extracted with 3×20 mL of DCM.The organic layers were combined and dried over anhydrous Na₂SO₄, thenconcentrated under vacuum. The residue was applied onto a silica gelcolumn and eluted with a gradient of ethyl acetate/petroleum ether (1:2to 1:3). This resulted in 0.55 g (41%) of the title compound as a lightyellow solid. MS-ESI: 270.1 (M+1).

Step 6: 8-(Difluoromethoxy)-1,2,3,5,6,7-hexahydro-s-indacen-4-amine

Into a 100-mL round-bottom flask was placed a solution of4-(difluoromethoxy)-8-nitro-1,2,3,5,6,7-hexahydro-s-indacene (550 mg,2.0 mmol) in MeOH (10 mL). Then Pd/C (10% wt., 100 mg) was added. Theflask was evacuated and filled three times with hydrogen. The resultingsolution was stirred for 12 h at RT under an atmosphere of hydrogen. Thesolids were filtered out. The resulting filtrate was concentrated undervacuum. This resulted in 460 mg (94%) of the title compound as a lightyellow solid. MS-ESI: 240.1 (M+1).

Step 1: 2,6-Dibromo-4-chloro-3-fluoroaniline

Into a 500-mL round-bottom flask was placed 4-chloro-3-fluoroaniline(5.08 g, 34.9 mmol), ACN (200 mL), and NBS (18.69 g, 105.0 mmol). Theresulting solution was stirred for 12 h at RT and then was concentratedunder vacuum. The residue was applied onto a silica gel column andeluted with a gradient of ethyl acetate/petroleum ether (1:200 to1:100). This resulted in 9.7 g (92%) of the title compound as a lightyellow solid. MS-ESI: 303.8/305.8/301.8 (M+1).

Step 2: 4-Chloro-3-fluoro-2,6-bis(prop-1-en-2-yl)aniline

Into a 500-mL round-bottom flask purged with and maintained undernitrogen was placed a solution of 2,6-dibromo-4-chloro-3-fluoroaniline(9.03 g, 29.8 mmol) in 1,4-dioxane (200 mL) and water (20 mL). To thesolution were added4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (15.12 g,89.98 mmol), Cs₂CO₃ (29.34 g, 90.1 mmol) and Pd(dppf)C₁₂ (2.20 g, 3.0mmol). The resulting solution was stirred for 12 h at 90° C. and thenwas concentrated under vacuum. The residue was applied onto a silica gelcolumn and eluted with a gradient of ethyl acetate/petroleum ether (1:30to 1:20). This resulted in 4.3 g (64%) of the title compound as yellowoil. MS-ESI: 226.1, 228.1 (M+1).

Step 3: 3-Fluoro-2,6-bis(propan-2-yl)aniline

Into a 100-mL round-bottom flask was placed a solution of4-chloro-3-fluoro-2,6-bis(prop-1-en-2-yl)aniline (1 g, 4.4 mmol) in MeOH(15 mL). Then Pd/C (10% wt., 100 mg) was added. The flask was evacuatedand filled three times with hydrogen. The resulting solution was stirredfor 3 h at RT under an atmosphere of hydrogen. The solids were filteredout. The resulting filtrate was concentrated under vacuum. The residuewas applied onto a silica gel column and eluted with a gradient of ethylacetate/petroleum ether (1:5 to 1:3). This resulted in 700 mg (81%) ofthe title compound as light yellow oil. MS-ESI: 196.1 (M+1).

4-Isocyanato-1,2,3,5,6,7-hexahydro-s-indacene Step 1:4-Isocyanato-1,2,3,5,6,7-hexahydro-s-indacene

Into a 50-mL round-bottom flask purged with and maintained undernitrogen was placed 1,2,3,5,6,7-hexahydro-s-indacen-4-amine (64 mg, 0.4mmol), THF (5 mL) and BTC (37 mg, 0.1 mmol). The resulting solution wasstirred for 2 h at 65° C. and then was concentrated under vacuum. Thisresulted in 75 mg (crude) of the title compound as light brown oil. Thecrude product was used directly in the next step.

TABLE 9 The Intermediates in the following Table were prepared usingsimilar procedure as shown in Scheme 30 above for converting compound130″ to Intermediate 44. Intermediate # Structure IUPAC NameIntermediate 45

5-Fluoro-2-isocyanato-1,3-diisopropylbenzene Intermediate 46

2-Fluoro-4-isocyanato-3,5-diisopropylbenzonitrile Intermediate 47

5-(Difluoromethoxy)-2-isocyanato-1,3- diisopropylbenzene Intermediate 48

5-(Difluoromethoxy)-1-ethyl-2-isocyanato-3- isopropylbenzeneIntermediate 49

1-Cyclopropyl-5-(difluoromethoxy)-2-isocyanato- 3-isopropylbenzeneIntermediate 50

4-Chloro-8-isocyanato-1,2,3,5,6,7-hexahydro-s- indacene Intermediate 51

4-Fluoro-8-isocyanato-1,2,3,5,6,7-hexahydro-s- indacene Intermediate 52

5-Cyclopropyl-2-fluoro-4-isocyanato-3- isopropylbenzonitrileIntermediate 53

4-Isocyanato-3,5-diisopropylbenzonitrile Intermediate 54

1,2,3,5,6,7-Hexahydro-8-isocyanato-s-indacene- 4-carbonitrileIntermediate 55

4-(Difluoromethoxy)-1,2,3,5,6,7-hexahydro-8- isocyanato-s-indaceneIntermediate 56

1-Fluoro-3-isocyanato-2,4-diisopropylbenzene Intermediate 57

l,2,3,5,6,7-Hexahydro-8-isocyanato-1-methyl-s- indacene Intermediate 58

l,2,3,5,6,7-Hexahydro-4-isocyanato-1-methyl-s- indacene

The following schemes illustrate additional general methods for thesynthesis of compounds of Formula AA:

Scheme for the preparation of Sulfonimidamide Intermediates: Schemesbelow illustrate the preparation of sulfonimidamide intermediates 59-88and 112-113.

N′-(tert-butyldimethylsilyl)-5-(2-hydroxypropan-2-yl)-1-phenyl-1H-pyrazole-3-sulfonimidamideStep 1: Ethyl 3-nitro-1-phenyl-1H-pyrazole-5-carboxylate

Into a 250-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was placed ethyl3-nitro-1H-pyrazole-5-carboxylate (5.0 g, 27.0 mmol), THF (150 mL),phenylboronic acid (6.6 g, 54.1 mmol), Cu(OAc)₂ (7.38 g, 40.6 mmol), andpyridine (8.54 g, 108 mmol). The resulting solution was stirredovernight at RT. The resulting mixture was concentrated under vacuum.The residue was eluted from a silica gel column with ethylacetate/petroleum ether (1:1). This resulted in 3.1 g (44%) of the titlecompound as an off-white solid. MS-ESI: 262 (M+1).

Step 2: Ethyl 3-amino-1-phenyl-1H-pyrazole-5-carboxylate

Into a 100-mL round-bottom flask, was placed ethyl3-nitro-1-phenyl-1H-pyrazole-5-carboxylate (3.92 g, 15.0 mmol), MeOH (50mL), and Pd/C (wet 10% wt., 400 mg). The flask was evacuated and filledthree times with hydrogen. The resulting solution was stirred overnightat RT. The solids were filtered out. The resulting mixture wasconcentrated under vacuum. This resulted in 2.8 g (81%) of the titlecompound as a light yellow solid. MS-ESI: 232 (M+1).

Step 3: Ethyl 3-(chlorosulfonyl)-1-phenyl-1H-pyrazole-5-carboxylate

Into a 100-mL round-bottom flask, was placed ethyl3-amino-1-phenyl-1H-pyrazole-5-carboxylate (1.8 g, 7.78 mmol), HCl (cc.6.0 mol/L, 15 mL). This was followed by the addition of a solution ofNaNO₂ (646 mg, 9.36 mmol) in water (2.0 mL) dropwise with stirring at−10° C. The resulting solution was stirred for 30 min at −10° C. Theabove mixture was added to a saturated solution of SO₂ in AcOH (20 mL)dropwise with stirring at 0° C. Then to the above was added CuCl₂ (1.05g, 7.81 mmol). The resulting solution was stirred for 1 h at RT. Thereaction was then quenched by the addition of 30 mL of water. Theresulting solution was extracted with 3×30 mL of DCM and the organiclayers combined and dried over anhydrous sodium sulfate and concentratedunder vacuum. This resulted in 2.2 g (90%) of the title compound as alight yellow solid.

Step 4: Ethyl 1-phenyl-3-sulfamoyl-1H-pyrazole-5-carboxylate

Into a 100-mL round-bottom flask, was placed a solution of ethyl3-(chlorosulfonyl)-1-phenyl-1H-pyrazole-5-carboxylate (2.2 g, 6.99 mmol)in DCM (10 mL). Then to the above was introduced NH₃ gas bubbled at 0°C. for 10 min. The resulting solution was stirred for 2 h at RT. Theresulting mixture was concentrated under vacuum. The residue was elutedfrom a silica gel column with ethyl acetate/petroleum ether (1:1). Thisresulted in 1.07 g (52%) of the title compound as a light yellow solid.MS-ESI: 296 (M+1).

Step 5: 5-(2-Hydroxypropan-2-yl)-1-phenyl-1H-pyrazole-3-sulfonamide

Into a 100-mL 3-necked round-bottom flask purged and maintained with aninert atmosphere of nitrogen, was placed a solution of ethyl1-phenyl-3-sulfamoyl-1H-pyrazole-5-carboxylate (1.65 g, 5.59 mmol) inTHF (30 mL). This was followed by the addition of MeMgBr/THF (3.0 M,18.6 mL) dropwise with stirring at 0° C. The resulting solution wasstirred overnight at RT. The reaction was then quenched by the additionof 30 mL of NH₄Cl (sat.). The resulting solution was extracted with 3×30mL of DCM and the organic layers combined and dried over anhydroussodium sulfate and concentrated under vacuum. The residue was elutedfrom a silica gel column with ethyl acetate/petroleum ether (2:1). Thisresulted in 1.35 g (86%) of the title compound as a yellow solid.MS-ESI: 282 (M+1).

Step 6:N-(tert-butyldimethylsilyl)-5-(2-hydroxypropan-2-yl)-1-phenyl-1H-pyrazole-3-sulfonamide

Into a 100-mL round-bottom flask, was placed5-(2-hydroxypropan-2-yl)-1-phenyl-1H-pyrazole-3-sulfonamide (500 mg,1.78 mmol), THF (10 mL). This was followed by the addition of sodiumhydride (60% wt. oil dispersion, 86 mg, 3.58 mmol) in portions at 0° C.Then to the above was added TBSCl (538 mg, 3.57 mmol). The resultingsolution was stirred for 2 h at RT. The reaction was then quenched bythe addition of 10 mL of water. The resulting solution was extractedwith 3×10 mL of DCM. The organic layers were combined, dried overanhydrous sodium sulfate, and concentrated under vacuum. The residue waseluted from a silica gel column with ethyl acetate/petroleum ether(1:2). This resulted in 660 mg (94%) of the title compound as a lightyellow solid. MS-ESI: 396 (M+1).

Step 7:N′-(tert-butyldimethylsilyl)-5-(2-hydroxypropan-2-yl)-1-phenyl-1H-pyrazole-3-sulfonimidamide

Into a 100-mL 3-necked round-bottom flask purged and maintained with aninert atmosphere of nitrogen, was placed the solution of PPh₃Cl₂ (1.67g, 5.01 mmol) in chloroform (30 mL). This was followed by the additionof DIEA (1.29 g, 9.98 mmol) dropwise with stirring at RT. The resultingsolution was stirred for 10 min at RT and the reaction system was cooledto 0° C. To this was added a solution of N-(tert-butyldimethylsilyl)-5-(2-hydroxypropan-2-yl)-1-phenyl-1H-pyrazole-3-sulfonamide (660mg, 1.67 mmol) in chloroform (3.0 mL) dropwise with stirring at 0° C.The resulting solution was stirred for 30 min at 0° C. To the mixturewas added introduced NH₃ gas bubble for 15 min at 0° C. The resultingsolution was stirred for 2 h at RT. The resulting solution was dilutedwith 30 mL of water. The resulting solution was extracted with 3×30 mLof DCM and the organic layers combined and dried over anhydrous sodiumsulfate and concentrated under vacuum. The residue was eluted from asilica gel column with ethyl acetate/petroleum ether (1:1). Thisresulted in 530 mg (81%) of the title compound as a light yellow solid.MS-ESI: 395 (M+1).

N′-(tert-butyldimethylsilyl)-4-(2-hydroxypropan-2-yl)-5-methylthiazole-2-sulfonimidamide

Steps 1-6 used similar procedures for converting compound 16 tointermediate 2 shown in Scheme 7B to afford intermediate 60 fromcompound 151″. MS-ESI: 350 (M+1).

N-methyl-N-(4-sulfamoylbenzyl)acetamide

N-(4-(N′-(tert-butyldimethylsilyl)sulfamidimidoyl)benzyl)-N-methylacetamide Step 1:N-benzyl-N-methylacetamide

Into a 1.0 L round-bottom flask were added benzyl(methyl)amine (10 g,82.5 mmol) and DCM (500 mL) at 0° C. To this stirred solution were addedDIEA (21.3 g, 165 mmol) and acetyl chloride (9.72 g, 124 mmol) inportions at 0° C. The resulting mixture was stirred for 4 h at RT. Theresulting mixture was concentrated under reduced pressure. The residuewas eluted from a silica gel column with ethyl acetate/petroleum ether(1:1) to afford the title compound (13 g, 96.5%) as a yellow oil.MS-ESI: 164 (M+1).

Step 2: 4-((N-methylacetamido)methyl)benzenesulfonyl chloride

Into a 250 mL round-bottom flask were added N-benzyl-N-methylacetamide(3.0 g, 18.4 mmol,) and DCM (6.0 mL) at 0° C. To this stirred solutionwere added C₁SO₂₀H (6.0 mL) in one portion at 0° C. The resultingmixture was stirred for 3 h at RT. The reaction was quenched by theaddition of water/ice (150 mL) at 0° C. The resulting solution wasextracted with 3×150 mL of DCM and the organic layers combined and driedover anhydrous sodium sulfate and concentrated under vacuum. The crudeproduct of the title compound (2.2 g, 45.7%)) was used in the next stepdirectly without further purification.

Step 3: N-methyl-N-(4-sulfamoylbenzyl)acetamide

Into a 250 mL round-bottom flask were added4-[(N-methylacetamido)methyl]benzene-1-sulfonyl chloride (2.2 g, 8.41mmol) and DCM (3.0 mL) at 0° C. To this stirred solution were added NH₃(g) in DCM (40 mL) dropwise at 0° C. The resulting mixture was stirredovernight at RT. The resulting mixture was concentrated under reducedpressure. The residue was eluted from a silica gel column with ethylacetate/petroleum ether (1:1) to afford the minor compound 159B (122 mg,6.1%) and the title compound (1.9 g, 93.3%) both as white solids.MS-ESI: 243 (M+1).

Step 4-6 used similar procedures for converting compound 148″ tointermediate 59 shown in Scheme 36 to afford intermediate 62 fromintermediate 61. MS-ESI: 356 (M+1)

TABLE 10 Intermediate 62B in the following Table was prepared using thesimilar procedures for converting compound 157″ to Intermediate 62 shownin Scheme 38 from compound 159″B which 5 was separated from step 3 inScheme 38. The Intermediate 63 was prepared using similar procedures forconverting compound 157″ to Intermediate 62 shown in Scheme 38 fromappropriate starting materials. Exact Intermediate # Structure IUPACName Mass[M + H]⁺ Intermediate 62B

N-(3-(N′-(tert-butyldimethylsilyl) sulfamimidoyl)benzyl)-N-methylacetamide 356 Intermediate 63

N′-(tert-butyldimethylsilyl)-2-fluoro- 4-methoxybenzenesulfonimidamide319

4-((Methylamino)methyl)benzenesulfonamide

N-(4-(N′-(tert-butyldimethylsilyl)sulfamimidoyl)benzyl)-N-methylpent-4-ynamide Step 1:4-((Methylamino)methyl)benzenesulfonamide

Into a 500-mL sealed tube, was placedN-methyl-N-[(4-sulfamoylphenyl)methyl]acetamide (5.0 g), hydrogenchloride (200 mL, 12 M). The resulting solution was stirred for 16 h at100° C. in an oil bath. The resulting mixture was concentrated. Thisresulted in 5.0 g of the title compound as an off-white crude solid.MS-ESI: 201 (M+1)

Step 2: N-methyl-N-(4-sulfamoylbenzyl)pent-4-ynamide

Into a 250 mL round-bottom flask was placed4-((methylamino)methyl)benzenesulfonamide (4.0 g, 20 mmol) in DMF (40mL). To this stirred solution was added HATU (6.33 g, 16.7 mmol), DIEA(5.16 g, 40 mmol) and pent-4-ynoic acid (2.16 g, 22 mmol). Then themixture was stirred overnight RT. The resulting solution was dilutedwith 40 mL of water. The resulting solution was extracted with 3×50 mLof ethyl acetate and the organic layers combined and dried overanhydrous sodium sulfate and concentrated under vacuum. The residue waseluted from a silica gel column with ethyl acetate/petroleum ether(1:1). This resulted in 2.97 g (53%) of the title compound as a lightyellow solid. MS-ESI: 281 (M+1).

Steps 3-5 used similar procedures for converting Intermediate 61 toIntermediate 62 shown in Scheme 38 to afford Intermediate 65 fromcompound 163″. MS-ESI: 394 (M+1).

Tert-butyl4-(N′-(tert-butyldimethylsilyl)sulfamimidoyl)benzyl(methyl)carbamate

N′-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-((methylamino)methyl)benzenesulfonimidamideStep 1: Tert-butyl methyl(4-sulfamoylbenzyl)carbamate

Into a 250-mL round-bottom flask, was placed4-[(methylamino)methyl]benzene-1-sulfonamide (5.0 g, 25 mmol) in DCM(100 mL). To this stirred solution was added di-tert-butyl dicarbonate(6.0 g, 27.5 mmol). The resulting solution was stirred for 5 h at RT.The resulting mixture was concentrated. The residue was eluted from asilica gel column with ethyl acetate/petroleum ether (1:1). Thisresulted in 5.0 g (66.7%) of the title compound as a light yellow solid.MS-ESI: 301 (M+1).

Steps 2-4 used similar procedures for converting compound 148″ tointermediate 59 shown in Scheme 36 to afford Intermediate 66 fromcompound 166″. MS-ESI: 414 (M+1).

Step 5:Tert-butyl(4-(N-(tert-butyldimethylsilyl)-N′-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-sulfamidimidoyl)benzyl)(methyl)carbamate

Into a 50-mL round-bottom flask, was placed tert-butyl(4-(N′-(tert-butyldimethylsilyl)sulfamidimidoyl)benzyl)(methyl)carbamate(500 mg, 1.21 mmol) in THF (15 mL). To this stirred solution was added4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (343 mg, 1.81 mmol) andNaH (60% wt. oil dispersion, 96.8 mg, 2.42 mmol). The resulting solutionwas stirred for 3 h at RT. The reaction was quenched by the addition ofMeOH (10 mL). This resulted in 500 mg (67.5%) of the title compound as awhite crude solid. MS-ESI: 613 (M+1).

Step 6:N′-(1,2,3,5,6,7-hexahydro-s-indacen-4-ylcarbamoyl)-4-((methylamino)methyl)benzenesulfonimidamide

Into a 50-mL round-bottom flask was placed tert-butylN-[(4-[[(tert-butyldimethylsilyl)amino]([[(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl]imino])oxo-λ⁶-sulfanyl]phenyl)methyl]-N-methylcarbamate(90 mg) and HCl in dioxane (4 M, 5.0 mL). The resulting solution wasstirred for 16 h at RT. The resulting mixture was concentrated. Thecrude product was purified by Prep-HPLC with the following conditions:Column, Sunfire Prep C18 OBD, 10 um, 19*250 mm; mobile phase A: water(0.05% TFA) and B: ACN (20% to 50% gradient of B over 17 min); Detector,UV 220/254 nm. This resulted in 30 mg of the title compound as a whitesolid. MS-ESI: 399 (M+1).

N′-(tert-butyldimethylsilyl)-6-(2-hydroxypropan-2-yl)-2-methylpyridine-3-sulfonimidamideStep 1: Methyl 5-amino-6-methylpicolinate

Into a 50-mL seal tube was placed methyl 6-bromo-2-methylpyridin-3-amine(500 mg, 2.67 mmol) in MeOH (15 mL) and Pd(OAc)₂ (120 mg, 0.53 mmol),dppf (444 mg, 0.80 mmol), TEA (809 mg, 8.01 mmol). The seal tube wasevacuated and flushed three times with CO. The resulting solution wasstirred for 5 h at 100° C. under 10 atm of CO. Then the solution wasconcentrated under vacuum. The residue was eluted from a silica gelcolumn with ethyl acetate/petroleum ether (1:1). This resulted in 351 mg(79.2%) of the title compound as a light yellow solid. MS-ESI: 167(M+1). Steps 2-4 used similar procedures for converting compound 27 toIntermediate 30 shown in Scheme 9 to afford compound 176″ from compound173″. MS-ESI: 231 (M+1). Steps 5-6 used similar procedures forconverting compound 148″ to intermediate 59 shown in Scheme 36 to affordIntermediate 70 from compound 176″. MS-ESI: 344 (M+1).

TABLE 11 The Intermediates in the following Table were prepared usingthe similar procedures for converting compound 172″ to Intermediate 70shown in Scheme 42 from appropriate starting materials. ExactIntermediate # Structure IUPAC Name Mass[M + H]⁺ Intermediate 71

N′-(tert-butyldimethylsilyl)-6-(2- hydroxypropan-2-yl)pyridine-3-sulfonimidamide 330

N′-(tert-butyldimethylsilyl)-4-(2-methoxypropan-2-yl)benzenesulfonimidamide Step 1:1-Bromo-4-(2-methoxypropan-2-yl)benzene

Into a 250-mL round-bottom flask, was placed a solution of2-(4-bromophenyl)propan-2-ol (10 g, 46.5 mmol) in THF (50 mL). To thisstirred solution was added NaH (60% wt. oil dispersion, 5.19 g, 93 mmol)at 0° C. The resulting solution was stirred for 30 min at 0° C. To thisstirred solution was added MeI (6.60 g, 46.5 mmol) dropwise withstirring at 0° C. The resulting solution was allowed to react for anadditional 15 h at RT. The resulting solution was quenched with 40 mL ofwater. The resulting solution was extracted with 3×50 mL of ethylacetate and the organic layers combined and dried over anhydrous sodiumsulfate and concentrated under vacuum. The residue was eluted from asilica gel column with ethyl acetate/petroleum ether (15/85). Thisresulted in 8.5 g (50.3%) of the title compound as a yellow solid.

Step 2: 4-(2-Methoxypropan-2-yl)benzenesulfinic acid

Into a 250-mL 3-necked round-bottom flask purged and maintained with aninert atmosphere of nitrogen, was placed a solution of1-bromo-4-(2-methoxypropan-2-yl)benzene (5.0 g, 21.8 mmol) in THF (50mL). To this stirred solution was added n-BuLi (13 mL, 32.7 mmol, 2.5 M)dropwise with stirring at −78° C. The resulting solution was stirred for30 min at −78° C. SO₂(g) was introduced into the stirring solution at−78° C. The resulting solution was allowed to react for an additional 60min at RT. The resulting mixture was concentrated. This resulted in 6.0g (crude) of the title compound as a yellow solid. MS-ESI: 213 (M−1)

Step 3: 4-(2-Methoxypropan-2-yl)benzenesulfonyl chloride

Into a 50-mL round-bottom flask, was placed4-(2-methoxypropan-2-yl)benzene-1-sulfinic acid (4.9 g, 22.9 mmol) inTHF (50 mL). To this stirred solution was added NCS (4.58 g, 34.3 mmol).The resulting solution was stirred for 30 min at 0° C. The mixture wasallowed to react for an additional 60 min at RT. NH₃ (g) was introducedinto the reaction solution. The resulting solution was allowed to reactfor an additional 120 min at RT. The resulting mixture was concentrated.The residue was eluted from a silica gel column with ethylacetate/petroleum ether (1/4). This resulted in 4.3 g (82%) of the titlecompound as a yellow solid.

Step 4: 4-(2-Methoxypropan-2-yl)benzenesulfonamide

Into a 250-mL round-bottom flask was placed4-(2-methoxypropan-2-yl)benzene-1-sulfonyl chloride (4.3 g, 17.3 mmol)in DCM (50 mL). NH₃ (g) was introduced into the reaction solution at 0°C. The resulting solution was stirred for 180 min at RT. The resultingmixture was concentrated. The residue was eluted from a silica gelcolumn with ethyl acetate/petroleum ether (1/3). This resulted in 3.9 g(98.5%) of the title compound as a yellow solid. MS-ESI: 230 (M+1).

Step 5:N-(tert-butyldimethylsilyl)-4-(2-methoxypropan-2-yl)benzenesulfonamide

Into a 100-mL round-bottom flask, was placed a solution of4-(2-methoxypropan-2-yl)benzene-1-sulfonamide (4.0 g, 17.5 mmol) in THF(40 mL). To this stirred solution was added NaH (1.4 g, 34.9 mmol, 60%wt. oil dispersion) and TBSCl (3.16 g, 21 mmol) at 0° C. The resultingsolution was allowed to react with stirring for 15 h at RT. Theresulting solution was quenched with 40 mL of water. The resultingsolution was extracted with 3×50 mL of ethyl acetate and the organiclayers combined and dried over anhydrous sodium sulfate and concentratedunder vacuum. The residue was eluted from a silica gel column with ethylacetate/petroleum ether (30/70). This resulted in 2.3 g (38.4%) of thetitle compound as a yellow solid. MS-ESI: 344 (M+1)

Step 6:N′-(tert-butyldimethylsilyl)-4-(2-methoxypropan-2-yl)benzenesulfonimidamide

Into a 500-mL 3-necked round-bottom flask purged and maintained with aninert atmosphere of nitrogen, was placed the solution of PPh₃Cl₂ (12.4g, 37.3 mmol) in chloroform (150 mL). This was followed by the additionof DIEA (9.63 g, 74.5 mmol) dropwise with stirring at RT. The resultingsolution was stirred for 10 min at RT and the reaction system was cooledto 0° C. To this was added a solution ofN-(tert-butyldimethylsilyl)-4-(2-methoxypropan-2-yl)benzene-1-sulfonamide(3.2 g, 9.31 mmol) in chloroform (30 mL) dropwise with stirring at 0° C.The resulting solution was stirred for 30 min at 0° C. To the mixturewas introduced NH₃ gas bubble for 15 min at 0° C. The resulting solutionwas stirred for 2 h at RT. The resulting solution was diluted with 100mL of water. The resulting solution was extracted with 3×200 mL of DCMand the organic layers combined and dried over anhydrous sodium sulfateand concentrated under vacuum. The residue was eluted from a silica gelcolumn with ethyl acetate/petroleum ether (36/64). This resulted in 1.4g (36.5%) of the title compound as a yellow solid. MS-ESI: 343 (M+1)

N′-(tert-butyldimethylsilyl)-5-((dimethylamino)methyl)pyridine-2-sulfonimidamideStep 1: (6-Bromopyridin-3-yl)-N,N-dimethylmethanamine

Into a 500-mL 3-necked round-bottom flask purged and maintained with aninert atmosphere of nitrogen, were placed Ti(OEt)₄ (12.3 g, 53.8 mmol)and dimethylamine (4.85 g, 108 mmol) in Me OH (50 mL) at RT. To astirred solution was added 6-bromopyridine-3-carbaldehyde (5.0 g, 26. 9mmol) in MeOH (30 mL) dropwise at 0° C. Then the reaction solution wasstirred at RT for 3 h. NaBH₄ (1.02 g, 26.9 mmol) was added to themixture and the resulting solution was stirred over night at RT. Thereaction was quenched by the addition of water/ice (30 mL) at 0° C. Theresult in g mixture was concentrated under reduced pressure. Then theresulting mixture extracted with ethyl acetate (3×50 mL) and the organiclayers combined and dried over anhydrous sodium sulfate and concentratedunder vacuum. The residue was eluted from a silica gel column with ethylacetate/petroleum ether (5:1) to afford the title compound (3.5 g,60.5%) as a yellow oil. MS-ESI: 216/218 (M+1).

Steps 2-6 used similar procedures for converting compound 179″ toIntermediate 72 shown in Scheme 43 to afford Intermediate 73 fromcompound 185. MS-ESI: 329 (M+1).

TABLE 12 The Intermediates in the following Table were prepared usingthe similar procedures for converting compound 184″ to Intermediate 73shown in Scheme 44 from appropriate starting materials. ExactIntermediate # Structure IUPAC Name Mass[M + H]⁺ Intermediate 74

N′-(tert-butyldimethylsilyl)-6- ((dimethylamino)methyl)pyridine-3-sulfonimidamide 329

N′-(tert-butyldimethylsilyl)-1-methyl-1H-indazole-5-sulfonimidamide

Steps 1-6 used similar procedures for converting compound 179″ toIntermediate 72 shown in Scheme 43 to afford Intermediate 75 fromcompound 190″. MS-ESI: 325 (M+1).

N′-(tert-butyldimethylsilyl)-4-(2-(dimethylamino)propan-2-yl)benzenesulfonimidamideStep 1: 4-(Prop-1-en-2-yl)benzenesulfonamide

Into a 250-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was placed 4-bromobenzene-1-sulfonamide (5.0 g,21.2 mmol) in dioxane (100 mL) and H₂O (15 mL). To this stirred solutionwas added 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane(14.2 g, 84.7 mmol), Pd(dppf)C₁₂ (4.65 g, 6.35 mmol) and Cs₂CO₃ (13.8 g,42.4 mmol). The resulting solution was stirred for 15 h at 100° C. Theresulting mixture was concentrated under reduced pressure. The residuewas eluted from a silica gel column with ethyl acetate/petroleum ether(40/60). This resulted in 3.6 g (86.2%) of the title compound as ayellow solid. MS-ESI: 198 (M+1).

Step 2: 2-Chloro-N-(2-(4-sulfamoylphenyl)propan-2-yl)acetamide

Into a 1.0-L round-bottom flask, was placed4-(prop-1-en-2-yl)benzene-1-sulfonamide (5.0 g, 25.4 mmol) in H₂SO₄ (50mL) and AcOH (250 mL). To the stirred solution was added2-chloroacetonitrile (38.3 g, 507 mmol). The resulting solution wasstirred for 30 min at 0° C. The resulting solution was allowed to reactfor an additional 15 h at RT. The pH value of the solution was adjustedto 7 with Na₂CO₃ (5.0 M). Then the resulting mixture was extracted withethyl acetate (3×200 mL) and the organic layers combined and dried overanhydrous sodium sulfate and concentrated under vacuum. The residue waseluted from a silica gel column with ethyl acetate/petroleum ether(2/3). This resulted in 4.2 g (57%) of the title compound as yellow oil.MS-ESI: 291 (M+1).

Step 3: 4-(2-Aminopropan-2-yl)benzenesulfonamide

Into a 250-mL round-bottom flask, was placed2-chloro-N-[2-(4-sulfamoylphenyl)propan-2-yl]acetamide (4.2 g, 14.5mmol) in CH₃COOH (15 mL) and ethanol (75 mL). To this stirred solutionwas added thiourea (1.32 g, 17.3 mmol). The resulting solution wasstirred for 16 h at 85° C. The resulting mixture was washed with 100 mlof H₂O and extracted with 3×250 mL of ethyl acetate and the organiclayers combined and dried over anhydrous sodium sulfate and concentratedunder vacuum. This resulted in 2.3 g (54.3%) of the title compound as ayellow solid. MS-ESI: 215 (M+1).

Step 4: 4-(2-(Dimethylamino)propan-2-yl)benzenesulfonamide

Into a 250-mL round-bottom flask, was placed4-(2-aminopropan-2-yl)benzene-1-sulfonamide (2.14 g, 9.99 mmol) in MeOH(50 mL). To this stirred solution was added HCHO (37% wt., 599 mg, 20mmol) and NaBH₃CN (1.86 g, 30 mmol). The resulting solution was stirredfor 120 min at RT. The resulting mixture was diluted with 100 mL ofwater and extracted with 3×250 mL of ethyl acetate and the organiclayers combined and dried over anhydrous sodium sulfate and concentratedunder vacuum The residue was eluted from a silica gel column with ethylacetate/petroleum ether (30/70). This resulted in 1.0 g (41.3%) of thetitle compound as a yellow solid. MS-ESI: 243 (M+1).

Steps 5-7 used similar procedures for converting compound 148″ tointermediate 59 shown in Scheme 36 to afford Intermediate 76 fromcompound 200. MS-ESI: 356 (M+1).

N′-(tert-butyldimethylsilyl)-4-(1-(dimethylamino)ethyl)benzenesulfonimidamide Step 1:(E)-4-(1-((tert-butylsulfinyl)imino)ethyl)benzenesulfonamide

Into a 250-mL 3-necked round-bottom flask purged and maintained with aninert atmosphere of nitrogen was added 2-methylpropane-2-sulfinamide(3.04 g, 25.1 mmol) in THF (50 mL). To this stirred solution was addedTi(OEt)₄(11.5 g, 50.2 mmol) and 4-acetylbenzene-1-sulfonamide (5.0 g,25.1 mmol) in portions at RT. The resulting mixture was stirred forovernight at 70° C. under nitrogen atmosphere. The reaction was quenchedwith Water (20 mL) at 0° C. The resulting mixture was extracted withethyl acetate (3×30 mL). The combined organic layers were dried overanhydrous Na₂SO₄. After filtration, the filtrate was concentrated underreduced pressure. The residue was purified by silica gel columnchromatography, eluted with ethyl acetate/petroleum ether (1:1) toafford the title compound (5.0 g, 75.8%) as a yellow solid. MS-ESI: 303(M+1).

Step 2: 4-(1-((Tert-butylsulfinyl)amino)ethyl)benzenesulfonamide

Into a 500 mL round-bottom flask were added4-[(1E)-1-[(2-methylpropane-2-sulfinyl)imino]ethyl]benzene-1-sulfonamide(4.65 g, 15.4 mmol) in THF (200 mL) at RT. To this stirred solution wasadded NaBH₄ (1.16 g, 30.8 mmol) in portions at 0° C. under nitrogenatmosphere. The resulting mixture was stirred for 4 h at RT undernitrogen atmosphere. The reaction was quenched by the addition of HCl(2M, 50 mL) at 0° C. The resulting mixture was extracted with ethylacetate (3×50 mL). The combined organic layers were dried over anhydrousNa₂SO₄. After filtration, the filtrate was concentrated under reducedpressure to afford the title compound (4.5 g, 96.1%) as a white solid.MS-ESI: 305 (M+1).

Step 3: 4-(1-Aminoethyl)benzenesulfonamide

Into a 250 mL round-bottom flask were added4-[1-[(2-methylpropane-2-sulfinyl)amino]ethyl]benzene-1-sulfonamide (4.4g, 14.5 mmol) and MeOH (50 mL) at room temperature. To this stirredsolution was added HCl (gas) in 1,4-dioxane (8.0 mL, 26.3 mmol) in oneportions at RT. The resulting mixture was stirred overnight at RT. Theresulting mixture was concentrated under reduced pressure. The residuewas purified by reverse flash chromatography with the followingconditions (column, C18 silica gel; mobile phase, MeCN in water, 10% to50% gradient in 10 min; detector, UV 254 nm.) to afford the titlecompound (2.6 g, 89.7%) as a white solid. MS-ESI: 201 (M+1).

Step 4: 4-(1-(Dimethylamino)ethyl)benzenesulfonamide

Into a 250 mL round-bottom flask was added4-(1-aminoethyl)benzene-1-sulfonamide (2.0 g, 9.99 mmol) and MeOH (60mL) at RT. To this stirred solution was added HCHO (37% wt., 1.61 g,53.6 mmol) and NaBH₃CN (1.25 g, 20 mmol) in portions at RT. Theresulting mixture was stirred overnight at RT. The reaction solution wasdiluted with 100 mL of water and extracted with 3×100 mL of ethylacetate and the organic layers combined and dried over anhydrous sodiumsulfate and concentrated under vacuum. The residue was eluted from asilica gel column with ethyl acetate/petroleum ether. The residue waspurified by silica gel column chromatography, eluted with ethylacetate/petroleum ether (1:2) to afford the title compound (1.5 g,65.8%) as a white solid. MS-ESI: 229 (M+1).

Steps 5-7 used similar procedures for converting compound 148″ tointermediate 59 shown in Scheme 36 to afford Intermediate 77 fromcompound 207″. MS-ESI: 342 (M+1).

4-(2-Hydroxypropan-2-yl)-N,N-dimethylthiophene-2-sulfonimidamide Step 1:N′-(tert-butyldimethylsilyl)-4-(2-hydroxypropan-2-yl)-N,N-dimethylthiophene-2-sulfonimidamide

Into a 50-mL 3-necked round-bottom flask, was placedN-(tert-butyldimethylsilyl)-4-(2-hydroxypropan-2-yl)thiophene-2-sulfonoimidamide (300 mg, 0.90 mmol) in THF (3.0 mL). To thesolution were added NaH (60% wt. oil dispersion, 53.8 mg, 1.35 mmol) at−10° C. in ethanol/ice bath. To the solution were added iodomethane(0.50 mL) dropwise with stirring at 0° C. in 30 min. The resultingsolution was stirred for 30 min at RT. The reaction was then quenched bythe addition of NH₄C₁ (aq.). The resulting solution was extracted with3×20 mL of ethyl acetate and the organic layers combined, dried overanhydrous sodium sulfate and concentrated under vacuum. The residue waseluted from a silica gel column with ethyl acetate/petroleum ether(1:5). This resulted in 252 mg (77.5%) of the title compound as a whitesolid. MS-ESI: 363 (M+1).

Step 2:N′-(tert-butyldimethylsilyl)-4-(2-hydroxypropan-2-yl)-N,N-dimethylthiophene-2-sulfonimidamide

Into a 50-mL round-bottom flask, was placedN-(tert-butyldimethylsilyl)-4-(2-hydroxypropan-2-yl)-N,N-dimethylthiophene-2-sulfonoimidamide(200 mg, 0.55 mmol) in THF (10 mL). To the solution was added HF/Py (70%wt., 0.10 mL) dropwise with stirring at RT. The resulting solution wasstirred for 60 min at RT. The resulting mixture was concentrated undervacuum. The resulting solution was extracted with ethyl acetate (3×10mL), the organic layers combined and dried over anhydrous sodiumsulfate. The residue was eluted from a silica gel column with ethylacetate. This resulted in 127 mg (92.7%) of the title compound as awhite solid. MS-ESI: 249 (M+1).

2-(2-Hydroxypropan-2-yl)-N-methylthiazole-5-sulfonimidamide Step 1:Tert-butyl(chloro(2-(2-hydroxypropan-2-yl)thiazol-5-yl)(oxo)-λ⁶-sulfaneylidene)carbamate

Into a 1.0-L round-bottom flask, was placed tert-butylN-[[2-(2-hydroxypropan-2-yl)-1,3-thiazol-5-yl]sulfinyl]carbamate (100 g,326 mmol) in ACN (500 mL). To the stirred solution was added NCS (65.4g, 490 mmol). The resulting solution was stirred for 2 h at RT. Theresulted solution was concentrated. This resulted in 120 g (crude) ofthe title compound as yellow oil. MS-ESI: 341/343 (M+1).

Step 2:Tert-butyl((2-(2-hydroxypropan-2-yl)thiazol-5-yl)(methylamino)(oxo)-λ⁶-sulfaneylidene)carbamate

Into a 250-mL round-bottom flask, was placed tert-butyl(chloro(2-(2-hydroxypropan-2-yl)thiazol-5-yl)(oxo)-λ⁶-sulfaneylidene)carbamate(10 g, 29.3 mmol) in THF (100 mL). To the stirred solution was addedCH₃NH₂ (1.82 g, 58.6 mmol). The resulting solution was stirred for 2 hat RT. The resulted solution was concentrated. The residue was elutedfrom a silica gel column with ethyl acetate/petroleum ether (1:1). Thisresulted in 6.1 g (62%) of the title compound as a yellow solid. MS-ESI:336 (M+1).

Step 3: 2-(2-Hydroxypropan-2-yl)-N′-methylthiazole-5-sulfonimidamide

Into a 100-mL round-bottom flask, was placedtert-butyl((2-(2-hydroxypropan-2-yl)thiazol-5-yl)(methylamino)(oxo)-λ⁶-sulfaneylidene)carbamate (3.0 g, 8.94 mmol) in HCl (gas) in 1,4-dioxane (8 mL, 26.3mmol) in one portion at RT. The resulting solution was stirred for 60min at RT. The resulting mixture was concentrated under vacuum. Thisresulted in 2.10 g (crude) of the title compound as a yellow solid.MS-ESI: 236 (M+1).

Tert-butyl(amino(2-(2-methoxypropan-2-yl)thiazol-5-yl)(oxo)-λ⁶-sulfaneylidene)carbamateStep 1: Methyl 2-(2-methoxypropan-2-yl)thiazole-5-sulfinate

Into a 1-L round-bottom flask, was placed a solution of methyl2-(2-hydroxypropan-2-yl)-1,3-thiazole-5-sulfinate (40 g, 181 mmol) inTHF (500 mL). To this stirred solution was added NaH (60% wt. oildispersion, 7.95 g, 199 mmol) in three portions at 0° C. in anice/ethanol bath. To this reaction solution was added MeI (51.3 g, 362mmol) dropwise with stirring at 0° C. in an ice/ethanol bath. Theresulting solution was stirred for 3 h at RT. The reaction was thenquenched by the addition of water (50 mL) at 0° C. The resultingsolution was extracted with 3×300 mL of ethyl acetate and the organiclayers combined and dried over anhydrous sodium sulfate and concentratedunder vacuum. This resulted in 32 g (75.3%) of the title compound as awhite solid. MS-ESI: 236 (M+1).

Step 2: 2-(2-Methoxypropan-2-yl)thiazole-5-sulfinamide

Into a 1-L 3-necked round-bottom flask purged and maintained with aninert atmosphere of nitrogen, was placed a solution of methyl2-(2-methoxypropan-2-yl)-1,3-thiazole-5-sulfinate (20 g, 85 mmol) in THF(500 mL). This was followed by the addition of KHMDS (500 mL, 1.0 mole,2 M) dropwise with stirring at −78° C. in a liquid nitrogen/ethanolbath. The resulting solution was stirred for 3 h at −78° C. in a liquidnitrogen/ethanol bath. The reaction was quenched by the addition ofwater (50 mL). The resulting solution was extracted with 3×300 mL ofethyl acetate dried over anhydrous sodium sulfate and concentrated undervacuum. The residue was eluted from a silica gel column with ethylacetate/petroleum ether (1:3). This resulted in 14 g (74.8%) of thetitle compound as a white solid. MS-ESI: 221.0 (M+1).

Step 3: Tert-butyl((2-(2-methoxypropan-2-yl)thiazol-5-yl)sulfinyl)carbamate

Into a 500-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was placed a solution of2-(2-methoxypropan-2-yl)-1,3-thiazole-5-sulfinamide (10 g, 45.4 mmol) inTHF (250 mL). To this stirred solution was added NaH (60% wt. oildispersion, 3.63 g, 90.8 mmol) in three times at 0° C. in an ice/ethanolbath. To this solution was added Boc₂O (9.91 g, 45.4 mmol) in portionsat 0° C. in an ice/ethanol bath. The resulting solution was stirred for3 h at RT. The reaction was then quenched by the addition of water (50mL). The resulting solution was extracted with 3×300 mL of ethyl acetateconcentrated under vacuum. This resulted in 12 g (82.5%) of the titlecompound as a white solid. MS-ESI: 321.1 (M+1).

Step 4: Tert-butyl(chloro(2-(2-methoxypropan-2-yl)thiazol-5-yl)(oxo)-λ⁶-sulfaneylidene)carbamate

Into a 500-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was placed a solution of tert-butylN-[[2-(2-methoxypropan-2-yl)-1,3-thiazol-5-yl]sulfinyl]carbamate (11 g,34.3 mmol) in THF (200 mL). NCS (13.8 g, 103 mmol) was added to thereaction solution in one portion at RT. The resulting solution wasstirred for 3 h at RT. This reaction solution was used to the next stepdirectly without further purification.

Step 5: Tert-butyl(amino(2-(2-methoxypropan-2-yl)thiazol-5-yl)(oxo)-λ⁶-sulfaneylidene)carbamate

Into a 500-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was placed a solution of tert-butylN-[[2-(2-methoxypropan-2-yl)-1,3-thiazol-5-yl]sulfinyl]carbamate (9.0 g,28.9 mmol) in THF (200 mL). To the mixture was added introduced NH₃ gasbubble for 15 min at 0° C. The resulting solution was stirred for 1 h atRT. The resulting mixture was concentrated. The residue was eluted froma silica gel column with ethyl acetate/petroleum ether (1:1). Thisresulted in 7 g (72.3%) of the title compound as a white solid. MS-ESI:336.1 (M+1).

N′-(tert-butyldimethylsilyl)-6-isobutylpyridine-3-sulfonimidamide

Steps 1-2 used similar procedures for converting compound 27 toIntermediate 29 shown in Scheme 9 to afford compound 219″ from compound217″. MS-ESI: 238 (M+1).

Step 3: 6-(2-Methylprop-1-enyl)pyridine-3-sulfonamide

Into a 500 mL round-bottom flash were added6-bromopyridine-3-sulfonamide (5.5 g, 23.2 mmol) and dioxane (150 mL)and water (15 mL) at RT. To this solution was added Pd(dppf)C₁₂ (1.7 g,2.32 mmol), Cs₂CO₃ (15.1 g, 46.4 mmol) and4,4,5,5-tetramethyl-2-(2-methylprop-1-en-1-yl)-1,3,2-dioxaborolane (8.45g, 46.4 mmol) in one portion at RT under nitrogen atmosphere. Theresulting mixture was stirred overnight at 100° C. under nitrogenatmosphere. The resulting mixture was concentrated under reducedpressure. The residue was purified by silica gel column chromatographywith ethyl acetate/petroleum ether (1:1) to afford title compound (4.0g, 81.2%) as a light yellow oil. MS-ESI: 213 (M+1).

Step 4: 6-Isobutylpyridine-3-sulfonamide

Into a 250 mL 3-necked round-bottom flask was added6-(2-methylprop-1-en-1-yl)pyridine-3-sulfonamide (4 g, 18.8 mmol) andMeOH (100 mL) at RT under nitrogen atmosphere. To this stirred solutionwas added Pd/C (wet 10% wt., 900 mg). The flask was evacuated and filledthree times with hydrogen. The resulting mixture was stirred overnightat RT under hydrogen atmosphere. The resulting mixture was filtered; thefilter cake was washed with MeOH (3×20 mL). The filtrate wasconcentrated under reduced pressure. The crude product of the titlecompound (3.8 g) was used to the next step directly without furtherpurification. MS-ESI: 215 (M+1). Steps 5-7 used similar procedures forconverting compound 148″ to intermediate 59 shown in Scheme 36 to affordintermediate 81 from compound 221″. MS-ESI: 328 (M+1).

TABLE 13 The Intermediates in the following Table were prepared usingthe similar procedures for converting compound 217″ to Intermediate 81shown in Scheme 51 from appropriate starting materials. IntermediateExact Mass # Structure IUPAC Name [M + H]⁺ Intermediate 82

N′-(tert-butyldimethylsilyl)-4- isobutylbenzenesulfonimidamide 327

N-(tert-butyldimethylsilyl)-4-((tert-butyldimethylsilyloxy)methyl)benzenesulfonimidamideExample 233 (Compound 342)

N′-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-(hydroxymethyl)benzenesulfonimidamide Step 1: 4-(Hydroxymethyl)benzenesulfonamide

Into a 100-mL round-bottom flask, was placed 4-sulfamoylbenzoic acid(1.0 g, 4.97 mmol) in THF (15 mL). This was followed by the addition ofBH₃-THF (14.3 mL, 149 mmol) dropwise with stirring at 0° C. in anice/ethanol bath. The resulting solution was stirred for 12 h at RT. Thereaction was then quenched by the addition of HCl (50 mL, 2 M) dropwisein an ice bath and stirred for 1 h at RT. The mixture was extracted with8×50 mL of ethyl acetate. The organic layers were combined andconcentrated. This resulted in 800 mg (86%) of the title compound as ayellow solid. MS-ESI: 188 (M+1).

Steps 2-3 used similar procedures for converting compound 148″ toIntermediate 59 shown in Scheme 36 to afford Intermediate 83 fromcompound 225″. MS-ESI: 415 (M+1). Steps 4-5 used similar procedures forconverting compound 166″ to Intermediate 67 shown in Scheme 40A toafford compound Example 233 from Intermediate 83. MS-ESI: 386 (M+1).

Intermediate 84

4-(Bromomethyl)-N′-(1,2,3,5,6,7-hexahydro-s-indacen-4-ylcarbamoyl)benzenesulfonimidamideStep 6:4-(Bromomethyl)-N′-(1,2,3,5,6,7-hexahydro-s-indacen-4-ylcarbamoyl)benzenesulfonimidamide

Into a 250-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was placed1-[amino[4-(hydroxymethyl)phenyl]oxo-λ⁶-sulfanylidene]-3-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea(1.0 g, 2.59 mmol) in THF (50 mL). To the stirred solution was addedPBr₃ (702 mg, 2.59 mmol) in portions. The resulting solution was stirredfor 3 h at RT. The solids were collected by filtration. This resulted in500 mg (43%) of the title compound as a white solid. MS-ESI: 449/411(M+1).

N′-(tert-butyldimethylsilyl)-2-methyl-1,2,3,4-tetrahydroisoquinoline-6-sulfonimidamideStep 1: 6-Bromo-2-methyl-1,2,3,4-tetrahydroisoquinoline

Into a 250-mL round-bottom flask, was placed6-bromo-1,2,3,4-tetrahydroisoquinoline (6.0 g, 28.3 mmol) in MeOH (100mL) under N₂. To the stirred solution was added HCHO (1.02 g, 34 mmol)in portions at RT. The resulting solution was stirred for 4 h, thenNaBH₃CN (3.56 g, 56.6 mmol) was added in portions at RT. The resultingsolution was stirred overnight at RT. The reaction was then quenched bythe addition of water (100 mL) and extracted with 3×150 mL ethylacetate. The organic layers were combined and dried over anhydroussodium sulfate and concentrated under vacuum. The crude product waseluted from a silica gel column with acetate/petroleum ether (1:1). Thisresulted in 5 g (78.2%) of the title compound as a white solid. MS-ESI:226/228 (M+1).

Steps 2-5 used similar procedures for converting compound 185″ toIntermediate 173″ shown in Scheme 44 to afford Intermediate 85 fromcompound 229. MS-ESI: 238 (M+1).

N′-(tert-butyldimethylsilyl)-2-methyl-1,2,3,4-tetrahydroisoquinoline-7-sulfonimidamideStep 1: 1-(3,4-Dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethanone

Into a 250-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was placed 1,2,3,4-tetrahydroisoquinoline (8.0g, 60.1 mmol) and 2,2,2-trifluoroacetic anhydride (25.2 g, 120 mmol).The resulting solution was stirred for 12 h at RT. The reaction was thenquenched by the addition of 100 mL of water/ice. The resulting solutionwas extracted with 3×100 mL of ethyl acetate and the organic layers werecombined and dried over anhydrous sodium sulfate and concentrated undervacuum. This resulted in 10 g (72.6%) of the title compound as a yellowsolid. MS-ESI: 230 (M+1).

Steps 2-3 used similar procedures for converting compound 158″ toIntermediate 61 shown in Scheme 38 to afford compound 236″ from compound234″. MS-ESI: 309 (M+1).

Step 4: 1,2,3,4-Tetrahydroisoquinoline-7-sulfonamide

Into a 100-mL round-bottom flask, was placed2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide(8.0 g, 26 mmol) in ethanol (12 mL) and H₂O (60 mL). To the stirredsolution was added KOH (7.28 g, 123 mmol) in one portion at RT. Theresulting solution was stirred for 12 h at RT. The resulting mixture wasconcentrated. The crude product was applied onto a silica gel columnwith DCM/MeOH (10:1). This resulted in 5.0 g (90.8%) of the titlecompound as a light yellow solid.

Step 5 used similar procedures for converting compound 228″ to compound229″ shown in Scheme 53 to afford compound 238″ from compound 237″.MS-ESI: 227 (M+1).

Steps 6-7 used similar procedures for converting compound 148″ tointermediate 59 shown in Scheme 36 to afford intermediate 86 fromcompound 238″. MS-ESI: 340 (M+1).

N′-(tert-butyldimethylsilyl)-2-methyl-1,2,3,4-tetrahydroisoquinoline-7-sulfonimidamideStep 1: 4-((Dimethylamino)methyl)-2-methoxybenzenesulfonamide

Into a 50-mL round-bottom flask, was placed4-[(dimethylamino)methyl]-2-fluorobenzene-1-sulfonamide (1 g, 4.31 mmol)and DMF (10 mL, 0.14 mmol). Then to the above was added sodium methoxide(2.16 g, 40 mmol). The resulting solution was stirred for 12 h at RT.The reaction was then quenched by the addition of 5.0 mL of water. Theresidue was eluted from a C18 column with ACN:H₂O (3:7). This resultedin 800 mg (76.1%) of the title compound as a yellow solid. MS-ESI: 245(M+1).

Steps 2-3 used similar procedures for converting compound 148″ tointermediate 59 shown in Scheme 36 to afford intermediate 87 fromcompound 240″. MS-ESI: 358 (M+1).

N′-(tert-butyldimethylsilyl)-5-((dimethylamino)methyl)-3-fluorothiophene-2-sulfonimidamideStep 1: (4-Fluorothiophen-2-yl)methanol

Into a 1000-mL round-bottom flask, was placed methyl4-fluorothiophene-2-carboxylate (10 g, 62.4 mmol) in ethanol (300 mL).Then to the above solution was added NaBH₄ (4.62 g, 125 mmol) inportions at 0° C. in an ice/ethanol bath. The resulting solution wasstirred for 30 min at 0° C. and then the reaction solution was allowedto react for an additional 16 h at RT. The reaction was then quenched bythe addition of 50 mL of water. Then the mixture was concentrated andextracted with 3×100 mL of ethyl acetate and the organic layers werecombined and dried over anhydrous sodium sulfate and concentrated undervacuum. This resulted in 6.4 g (77.6%) of the title compound as whiteoil. MS-ESI: 133 (M+1)

Step 2: 2-(Bromomethyl)-4-fluorothiophene

Into a 250-mL round-bottom flask, was placed(4-fluorothiophen-2-yl)methanol (8.5 g, 64.3 mmol) in DCM (70 mL). Tothe stirred solution was added PBr₃ (19.2 g, 70.8 mmol) dropwise at 0°C. in an ice/ethanol bath. The resulting solution was stirred for 30 minat 0° C. The resulting solution was allowed to react for an additional12 h at RT. The reaction was then quenched by the addition of 50 mL ofwater. Then the mixture was concentrated and extracted with 3×100 mL ofethyl acetate and the organic layers were combined and dried overanhydrous sodium sulfate and concentrated under vacuum. The residue waseluted from a silica gel column with ethyl acetate/petroleum ether(15/85). This resulted in 7.0 g (55.8%) of the title compound as yellowoil. MS-ESI: 194/196 (M+1).

Step 3: 1-(4-Fluorothiophen-2-yl)-N,N-dimethylmethanamine

Into a 250-mL round-bottom flask, was placed2-(bromomethyl)-4-fluorothiophene (7.4 g, 37.9 mmol) in CHCl₃ (50 mL).To the above solution was added butoxytributyl-14-azane sulfate (6.76 g,19 mmol) and DMA (37 mL, 425 mmol) with stirring at RT. The resultingsolution was stirred for 2 h at 60° C. The reaction was then quenched bythe addition of 50 mL of water. Then the mixture was concentrated andextracted with 3×100 mL of ethyl acetate and the organic layers werecombined and dried over anhydrous sodium sulfate and concentrated undervacuum. The residue was eluted from a silica gel column with ethylacetate/petroleum ether (17/83). This resulted in 6.0 g (99.5%) of thetitle compound as a yellow solid. MS-ESI: 160 (M+1).

Step 4: Lithium 5-((dimethylamino)methyl)-3-fluorothiophene-2-sulfinate

Into a 500-mL 3-necked round-bottom flask purged with and maintainedunder nitrogen, was placed a solution of[(4-fluorothiophen-2-yl)methyl]dimethylamine (6.2 g, 38.9 mmol) in THF(60 mL). This was followed by the addition of n-BuLi/THF (18.7 mL, 2.5M) dropwise with stirring at −78° C. in a liquid nitrogen/ethanol bath.The resulting solution was stirred for 30 min at −78° C. To the aboveSO₂(g) was introduced into the reaction solution at −78° C. Theresulting solution was allowed to react for an additional 2 h at RT. Theresulting mixture was concentrated. This resulted in 10 g (crude) of thetitle compound as a yellow solid. MS-ESI: 222 (M−1).

Step 5: 5-((Dimethylamino)methyl)-3-fluorothiophene-2-sulfonyl chloride

Into a 500-mL round-bottom flask, was placed a solution of5-[(dimethylamino)methyl]-3-fluorothiophene-2-sulfinic acid (10 g, 44.8mmol) in THF (100 mL). To the above solution was added NCS (7.18 g, 53.8mmol). The resulting solution was stirred for 30 min at 0° C. and thenallowed to react for an additional 2 h at RT. This reaction was used fornext step without purification.

Step 6: 5-((Dimethylamino)methyl)-3-fluorothiophene-2-sulfonamide

Into a 500-mL round-bottom flask, was placed a solution of5-[(dimethylamino)methyl]-3-fluorothiophene-2-sulfonyl chloride (10 g,38.8 mmol) in THF (100 mL). To the above NH₃ (g) was introduced at RT.The resulting solution was stirred for 30 min at RT. The resultingmixture was concentrated. The residue was eluted from a silica gelcolumn with ethyl acetate/petroleum ether (60/40). This resulted in 2.1g (22.7%) of the title compound as yellow oil. MS-ESI: 239 (M+1).

Step 7:N-(tert-butyldimethylsilyl)-5-((dimethylamino)methyl)-3-fluorothiophene-2-sulfonamide

Into a 100-mL round-bottom flask, was placed a solution of5-[(dimethylamino)methyl]-3-fluorothiophene-2-sulfonamide (1.8 g, 7.55mmol) in THF (30 mL) under N₂. To the above solution was added NaH (60%wt. oil dispersion, 640 mg, 15 mmol) with stirring at 0° C. Theresulting solution was stirred for 5 min at 0° C. This was followed bythe addition of TBSCl (1.37 g, 9.09 mmol) at 0° C. The resultingsolution was allowed to react for an additional 15 h at RT. The reactionwas then quenched by the addition of 20 mL of water. Then the mixturewas concentrated and extracted with 3×100 mL of ethyl acetate and theorganic layers were combined and dried over anhydrous sodium sulfate andconcentrated under vacuum. The residue was eluted from a silica gelcolumn with ethyl acetate/petroleum ether (1:1). This resulted in 2.0 g(75.2%) of the title compound as yellow oil. MS-ESI: 353 (M+1).

Step 8:N-(tert-butyldimethylsilyl)-5-((dimethylamino)methyl)-3-fluorothiophene-2-sulfonimidoylchloride

Into a 500-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen was placed a solution of PPh₃Cl₂ (29.5 g, 88.7mmol) in CHCl₃ (50 mL). To the above solution was added DIEA (17.2 g,133 mmol) dropwise in an ice/water bath. The solution was stirred at RTfor 20 minutes. This was followed by the addition ofN-(tert-butyldimethylsilyl)-5-[(dimethylamino)methyl]-3-fluorothiophene-2-sulfonamide(15.7 g, 44.4 mmol) in CHCl₃ (30 mL) at 0° C. The resulting solution wasallowed to react for an additional 30 min at 0° C. Then the reactionsolution was used for next step without purification.

Step 9:N′-(tert-butyldimethylsilyl)-5-((dimethylamino)methyl)-3-fluorothiophene-2-sulfonimidamide

Into a 500-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was placed[(tert-butyldimethylsilyl)imino](chloro)[5-[(dimethylamino)methyl]-3-fluorothiophen-2-yl]-λ⁶-sulfanone(16.5 g, 44.4 mmol) in CHCl₃ (80 mL). To the above NH₃(g) was introducedat 0° C. for 15 min. The resulting solution was stirred for 15 min at 0°C. and then allowed to react for an additional 15 h at RT. The resultingmixture was concentrated. The residue was eluted from a silica gelcolumn with ethyl acetate/petroleum ether (60/40). This resulted in 5.8g (37.2%) of the title compound as a yellow solid. MS-ESI: 352 (M+1).

N′-(tert-butyldimethylsilyl)-2-(2-hydroxypropan-2-yl)thiazole-5-sulfonimidamideStep 1: 2-(2-Hydroxypropan-2-yl)thiazole-5-sulfonimidamide

Into a 250-mL round-bottom flask, was placed a solution of tert-butyl2-(2-hydroxypropan-2-yl)thiazole-5-sulfonimidoylcarbamate (3.21 g, 10mmol) in HCl/dioxane (4 M, 50 mL). The resulting solution was stirredfor 1 h at RT. The solution was concentrated to give the title compound(3.2 g, crude, yellow oil). MS-ESI: 222 (M+1).

Step 2:N′-(tert-butyldimethylsilyl)-2-(2-hydroxypropan-2-yl)thiazole-5-sulfonimidamide

Into a 250-mL round-bottom flask, was placed2-(2-hydroxypropan-2-yl)thiazole-5-sulfonimidamide (3.2 g crude, 10mmol) in THF (100 mL), DIEA (3.87 g, 30 mmol) was added in at RT. ThenTBSCl (3.0 g, 20 mmol) was added to the solution in portions. Theresulting solution was stirred for 16 h at RT. The solution wasconcentrated and the crude product was purified by silica gel columnwith ethyl acetate/petroleum ether (1:1) to give the title compound (2.3g, yield 70%, yellow solid). MS-ESI: 336 (M+1).

2-(2-Hydroxypropan-2-yl)-N-methylthiazole-5-sulfonimidamide Step 1:Tert-butyl(chloro(2-(2-hydroxypropan-2-yl)thiazol-5-yl)(oxo)-λ⁶-sulfaneylidene)carbamate

Into a 1-L round-bottom flask, was placed tert-butylN-[[2-(2-hydroxypropan-2-yl)-1,3-thiazol-5-yl]sulfinyl]carbamate (100 g,326 mmol) in ACN (500 mL). To the stirred solution was added NCS (65.4g, 49 mmol). The resulting solution was stirred for 2 h at RT. Theresulted solution was concentrated. This resulted in 120 g crude titlecompound as yellow oil.

Step 2:Tert-((2-(2-hydroxypropan-2-yl)thiazol-5-yl)(methylamino)(oxo)-λ⁶-sulfaneylidene)carbamate

Into a 250-mL round-bottom flask, was placed tert-butylN-[chloro[2-(2-hydroxypropan-2-yl)-1,3-thiazol-5-yl]oxo-λ⁶-sulfanylidene]carbamate(10 g, 29.3 mmol) in THF (100 mL). To the stirred solution was addedCH₃NH₂ (1.82 g, 58.6 mmol). The resulting solution was stirred for 2 hat RT. The resulted solution was concentrated. The residue was elutedfrom silica gel with ethyl acetate/petroleum ether (1:1). This resultedin 6.1 g (62%) of the title compound as a yellow solid. MS-ESI: 336(M+1).

Step 3: 2-(2-Hydroxypropan-2-yl)-N′-methylthiazole-5-sulfonimidamide

Into a 100-mL round-bottom flask, was placedtert-butyl((2-(2-hydroxypropan-2-yl)thiazol-5-yl)(methylamino)(oxo)-λ⁶-sulfaneylidene)carbamate (3.0 g, 8.94 mmol) in HCl(gas) in 1,4-dioxane (8.0 mL, 26.3 mmol) in one portion at RT. Theresulting solution was stirred for 60 min at RT. The resulting mixturewas concentrated under vacuum. This resulted in 2.10 g crude titlecompound as a yellow solid. MS-ESI: 236 (M+1).

The schemes below illustrate the synthesis of Intermediates 89-96,101-104, 114-117A, and 118″-126″, which are isocyanate and precursorsthereof as well as other intermediates:

7-Nitro-6-vinyl-1H-indazole Step 1: 7-Nitro-1H-indazol-6-ol

Into a 25-mL round-bottom flask, was placed 1H-indazol-6-ol (500 mg,3.73 mmol). This was followed by the addition of H₂SO₄ (5.0 mL) inseveral batches at 0° C. To this was added KNO3 (377 mg, 3.73 mmol) inportions at 0° C. The resulting solution was stirred for 30 min at 0° C.in a water/ice bath. The reaction was then quenched by the addition of50 mL of water/ice. The solids were collected by filtration. Thisresulted in 350 mg (52.4%) of the title compound as a brown solid.MS-ESI: 180 (M+1).

Step 2: 7-Nitro-1H-indazol-6-yl trifluoromethanesulfonate

Into a 50-mL round-bottom flask, was placed 7-nitro-1H-indazol-6-ol (350mg, 1.95 mmol) in DCM (10 mL), TEA (593 mg, 5.86 mmol), Tf₂O (717 mg,2.54 mmol). The resulting solution was stirred for 16 h at RT. Theresulting solution was diluted with 20 mL of H₂O. The resulting solutionwas extracted with 3×20 mL of ethyl acetate dried over anhydrous sodiumsulfate and concentrated. The residue was eluted from a silica gelcolumn with ethyl acetate/petroleum ether (1:3). This resulted in 80 mg(13.2%) of the title compound as a yellow solid. MS-ESI: 312 (M+1).

Step 3: 7-Nitro-6-vinyl-1H-indazole

Into a 50-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was placed 7-nitro-1H-indazol-6-yltrifluoromethanesulfonate (100 mg, 0.32 mmol) in dioxane (10 mL) and H₂O(2.0 mL), Cs₂CO₃ (209 mg, 0.64 mmol),2-ethenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (59.4 mg, 0.39 mmol),Pd(dppf)C₁₂ (23.5 mg, 0.030 mmol). The resulting solution was stirredfor 16 h at 90° C. in an oil bath. Then the mixture was concentratedunder vacuum. The residue was eluted from a silica gel column with ethylacetate/petroleum ether (1:3). This resulted in 50 mg (82.6%) of thetitle compound as a yellow solid. MS-ESI: 190 (M+1).

6-Ethyl-1H-indazol-7-amine Step 4: 6-Ethyl-1H-indazol-7-amine

Into a 50-mL round-bottom flask, was placed6-ethenyl-7-nitro-1H-indazole (50 mg) in MeOH (10 mL), and Pd/C (10%wt., 5.0 mg). The flask was evacuated and flushed three times withhydrogen. The resulting solution was stirred for 12 h at RT under anatmosphere of hydrogen. The Pd/C catalysts were filtered out, thefiltrate was concentrated under vacuum. This resulted in 44 mg of thetitle compound as a yellow solid. MS-ESI: 162 (M+1).

6-Ethyl-2-methyl-2H-indazol-7-amine Step 1:2-Methyl-7-nitro-6-vinyl-2H-indazole

Into a 50-mL round-bottom flask, was placed6-ethenyl-7-nitro-1H-indazole (380 mg, 2.01 mmol) in acetone (20 mL),KOH (225 mg, 4.02 mmol). This was followed by the addition of MeI (342mg, 2.41 mmol) dropwise with stirring. The resulting solution wasstirred for 1 h at 0° C. in a water/ice bath. The resulting solution wasdiluted with 20 mL of H₂O. The resulting solution was extracted with3×30 ml of ethyl acetate dried over anhydrous sodium sulfate andconcentrated. The residue was eluted from a silica gel column with ethylacetate/petroleum ether (1:1). This resulted in 210 mg (51.5%) of 254″as a yellow solid and 180 mg (44%) of 255″ as a yellow solid. MS-ESI:208 (M+1).

Step 2: 6-Ethyl-2-methyl-2H-indazol-7-amine

Into a 50-mL round-bottom flask purged and maintained with an inertatmosphere of N₂, was placed 6-ethenyl-1-methyl-7-nitro-1H-indazole (210mg, 1.03 mmol) in MeOH (15 mL) and Pd/C (10% wt., 50 mg). The flask wasevacuated and flushed three times with hydrogen. The resulting solutionwas stirred for 12 h at RT under an atmosphere of hydrogen. The Pd/Ccatalysts were filtered out, and the filtrate was concentrated undervacuum. This resulted in 160 mg (88.4%) of the title compound as ayellow solid. MS-ESI:176 (M+1).

TABLE 14 The Intermediates in the following Table were prepared usingthe similar procedures for converting compound 254″ to Intermediate 91shown in Scheme 58 from 255″. Intermediate Exact Mass # Structure IUPACName [M + H]⁺ Intermediate 92

6-Ethyl-1-methyl-1H-indazol-7-amine 176

2,4,5,6-Tetrahydro-1H-cyclobuta[f]inden-3-amine Step 1:Bicyclo[4.2.0]octa-1(6),2,4-triene-3-carbaldehyde

Into a 500-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was placed3-bromobicyclo[4.2.0]octa-1(6),2,4-triene (70 g, 382 mmol) in THF (300mL). This was followed by the addition of n-BuLi (184 mL, 459 mmol)dropwise with stirring at about −70° C. After addition, the reactionmixture was stirred at this temperature for 30 min. To this solution wasadded DMF (36.3 g, 497 mmol) dropwise with stirring at −70° C. Theresulting solution was stirred for 30 min at −70° C. in a liquidnitrogen bath. The reaction was slowly warmed to RT and then quenched bythe addition of 100 mL of water. The resulting solution was extractedwith 3×200 ml of DCM. The organic layers combined and dried overanhydrous Na₂SO₄, and then the organic layers was concentrated. Thisresulted in 50 g (98.9%) of the title compound as light yellow oil.MS-ESI: 133 (M+1).

Step 2: (Z)-3-(bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl)acrylic acid

Into a 250-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was placedbicyclo[4.2.0]octa-1(6),2,4-triene-3-carbaldehyde (1.7 g, 12.9 mmol) inpyridine (20 mL), propanedioic acid (1.99 g, 19.2 mmol) and piperidine(110 mg, 1.29 mmol). The resulting solution was stirred for overnight at90° C. in an oil bath. The resulting mixture was concentrated. Thisresulted in 2.1 g (93.7%) of the title compound as a solid. MS-ESI: 173(M−1).

Step 3: 3-(Bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl)propanoic acid

Into a 250-mL round-bottom flask, was placed 2-(Z orE)-3-[bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl]prop-2-enoic acid (2.1 g,12.1 mmol) and Pd/C (10% wt., 200 mg). The flask was evacuated andflushed three times with hydrogen. The resulting solution was stirredfor 12 h at RT under an atmosphere of hydrogen. The Pd/C catalysts werefiltered out, the filtrate was concentrated under vacuum. This resultedin 2.1 g (98.9%) of the title compound as a solid. MS-ESI: 175 (M−1).

Step 4: 3-(Bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl)propanoyl chloride

Into a 250-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was placed3-[bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl]propanoic acid (10 g, 56.8mmol) in DCM (100 mL). This was followed by the addition of oxalylchloride (7.2 g, 56.8 mmol) dropwise with stirring at 0° C. Theresulting solution was stirred for 2 h at 0° C. in a water/ice bath. Theresulting mixture was concentrated. This resulted in 10 g (90.5%) of thetitle compound as light yellow oil.

Step 5: 1,2,5,6-Tetrahydro-4H-cyclobuta[f]inden-4-one

Into a 100-mL round-bottom flask, was placed3-[bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl]propanoyl chloride (5.0 g,25.7 mmol) in DCM (50 mL). This was followed by the addition of AlCl₃(3.4 g, 25.7 mmol) in portions at 0° C. for 10 min. The resultingsolution was stirred for 1 h at 0° C. in a water/ice bath. The reactionwas then quenched by the addition of 100 mL of water. The resultingsolution was extracted with 2×50 mL of DCM. The organic layers combinedand dried over anhydrous Na₂SO₄, then concentrated. The residue waseluted from a silica gel column with ethyl acetate/petroleum ether (1:20to 1:15). This resulted in 3.5 g (86.1%) of the title compound as awhite solid. ¹H NMR (300 MHz, CDCl₃) δ 7.45 (s, 1H), 7.17 (s, 1H), 3.22(m, 4H), 3.18-3.00

-   -   (m, 2H), 2.73-2.63 (m, 2H).

Step 6: 2,4,5,6-Tetrahydro-1H-cyclobuta[f]indene

Into a 500-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was placed1,2,5,6-tetrahydrocyclobuta[f]inden-4-one (20 g, 126 mmol) in THF (200mL). This was followed by the addition of BH₃-Me₂S (25.3 mL, 253 mmol,10 M) dropwise at 0° C. in an ice bath. The resulting solution wasstirred for 14 h at 70° C. in an oil bath. The reaction was thenquenched by the addition of 20 mL of MeOH. The resulting mixture wasconcentrated. The residue was eluted from a silica gel column with ethylacetate/petroleum ether (1:100 to 1:50). This resulted in 15 g (82.3%)of the title compound as colorless oil. ¹H NMR (300 MHz, CDCl₃) δ 6.95(s, 2H), 3.10 (s, 4H), 2.88 (t, J=7.4 Hz, 4H), 2.03 (p, J=7.4 Hz, 2H).

Step 7: 3-Iodo-2,4,5,6-tetrahydro-1H-cyclobuta[f]indene

Into a 500-mL round-bottom flask, was placed acetic acid (100 mL),2,4,5,6-tetrahydro-1H-cyclobuta[f]indene (15 g, 104 mmol) and NIS (35.1g, 156 mmol). The resulting solution was stirred for 3 h at 50° C. in anoil bath. The resulting solution was diluted with 200 mL of water. Themixture was extracted with 3×100 mL of DCM. The organic layers combinedand dried over anhydrous Na₂SO₄, then concentrated. The residue waseluted from a silica gel column with ethyl acetate/petroleum ether(1:100 to 1:80). This resulted in 5.0 g (17.8%) of the title compound asyellow oil.

Step 8: Tert-butyl(2,4,5,6-tetrahydro-1H-cyclobuta[f]inden-3-yl)carbamate

Into a 250-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was placed3-iodo-2,4,5,6-tetrahydro-1H-cyclobuta[f]indene (5.0 g, 18.5 mmol) intoluene (100 mL), tert-butyl carbamate (6.5 g, 55.5 mmol), X-phos (900mg, 1.85 mmol), Pd₂(dba)₃ (800 mg, 0.93 mmol), t-BuOK (6.2 g, 55.5mmol). The resulting solution was stirred for 14 h at 100° C. in an oilbath. The resulting mixture was concentrated. The residue was elutedfrom a silica gel column with ethyl acetate/petroleum ether (1:50 to1:20). This resulted in 3.0 g (83.3%) of the title compound as a whitesolid. MS-ESI: 260 (M+1).

¹H NMR (300 MHz, CDCl₃) δ 6.72 (s, 1H), 6.13 (br, 1H), 3.26 (d, J=4.5Hz, 2H), 3.01 (d, J=4.5 Hz, 2H), 2.90 (t, J=7.4 Hz, 2H), 2.75 (t, J=7.4Hz, 2H), 2.06 (p, J=7.4 Hz, 2H), 1.52 (s, 9H).

Step 9: 2,4,5,6-Tetrahydro-1H-cyclobuta[f]inden-3-amine

Into a 100-mL round-bottom flask, was placedtert-butyl2,4,5,6-tetrahydro-1H-cyclobuta[f]inden-3-ylcarbamate (3.0 g,11.6 mmol) in DCM (20 mL), 2,2,2-trifluoroacetic acid (5.0 mL). Theresulting solution was stirred for 2 h at RT. The resulting solution wasdiluted with 50 mL of water. The pH value of the solution was adjustedto 10 with sat. aqueous Na₂CO₃. The resulting solution was extractedwith 3×20 mL of DCM. The organic layers combined and dried overanhydrous Na₂SO₄, then concentrated. This resulted in 1.5 g (81.4%) ofthe title compound as a yellow solid. MS-ESI: 160 (M+1).

3,5,6,7-tetrahydro-2H-indeno[5,6-b]furan-4-amine Step 1:8-Nitro-2,3,5,6-tetrahydro-7H-indeno[5,6-b]furan-7-one

Into a 100-mL round-bottom flask, was placed2H,3H,5H,6H,7H-indeno[5,6-b]furan-7-one (4 g, 23 mmol,) in H₂SO₄ (20mL). This was followed by the addition of HNO₃ (2.13 g, 23 mmol, 68%)dropwise with stirring at 0° C. in an ice/ethanol bath. The resultingsolution was stirred for 1 h at 0° C. The reaction was then quenched bythe addition of 200 mL of water/ice. The solids were collected byfiltration. This resulted in 4.0 g (79.5%) of the title compound as alight brown solid. MS-ESI: 220 (M+1).

Step 2: 3,5,6,7-Tetrahydro-2H-indeno[5,6-b]furan-8-amine

Into a 100-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was placed8-nitro-2H,3H,5H,6H,7H-indeno[5,6-b]furan-7-one (4.0 g, 18.3 mmol) inMeOH (50 mL), TsOH (1.0 mL), Pd(OH)₂/C (20% wt., 1 g). The flask wasevacuated and flushed three times with hydrogen. The resulting solutionwas stirred for 16 h at RT under an atmosphere of hydrogen. The solidswere filtered out. The resulting mixture was concentrated. The residuewas dissolved in 50 mL of EA. The resulting mixture was washed with 2×50ml of NaHCO₃ and 3×40 ml of H₂O. The mixture was dried over anhydroussodium sulfate. The residue was eluted from a silica gel column withethyl acetate/petroleum ether (1:9). This resulted in 1.1 g (34.4%) ofthe title compound as a yellow solid. MS-ESI: 176 (M+1).

Step 3: 4-Bromo-3,5,6,7-tetrahydro-2H-indeno[5,6-b]furan-8-amine

Into a 50-mL round-bottom flask, was placed2H,3H,5H,6H,7H-indeno[5,6-b]furan-8-amine (1.1 g, 6.28 mmol) in ACN (30mL) and NBS (1.34 g, 7.53 mmol). The resulting solution was stirred for2 h at RT. The resulting mixture was concentrated. The residue waseluted from a silica gel column with ethyl acetate/petroleum ether(1:8). This resulted in 83 mg (52%) of the title compound as a yellowsolid. MS-ESI: 254 (M+1).

Step 4: 4-Bromo-3,5,6,7-tetrahydro-2H-indeno[5,6-b]furan

Into a 50-mL round-bottom flask, was placed4-bromo-2H,3H,5H,6H,7H-indeno[5,6-b]furan-8-amine (500 mg, 1.97 mmol) inethanol (15 mL) and acetic acid (3.0 mL, 0.050 mmol). To the abovesolution was added NaNO₂ (1.36 g, 19.7 mmol) in H₂O (3 mL) dropwise at0° C. The resulting solution was stirred for 2 h at RT. The resultingsolution was diluted with 30 mL of H₂O. The resulting solution wasextracted with 3×30 ml of ethyl acetate dried over anhydrous sodiumsulfate and concentrated. The residue was eluted from a silica gelcolumn with ethyl acetate/petroleum ether (1:10). This resulted in 100mg (21.3%) of the title compound as a yellow solid. MS-ESI: 239 (M+1).

Step 5: Tert-butyl(3,5,6,7-tetrahydro-2H-indeno[5,6-b]furan-4-yl)carbamate

Into a 50-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was placed4-bromo-2H,3H,5H,6H,7H-indeno[5,6-b]furan (120 mg, 0.50 mmol) in toluene(15 mL), t-BuOK (282 mg, 2.51 mmol), tert-butyl carbamate (588 mg, 5.02mmol), Xphos (47.8 mg, 0.10 mmol), and Pd₂(dba)₃CHCl₃ (104 mg, 0.10mmol). The resulting solution was stirred for 16 h at 100° C. in an oilbath. The resulting mixture was concentrated. The residue was elutedfrom a silica gel column with ethyl acetate/petroleum ether (1:5). Thisresulted in 80 mg (57.9%) of the title compound as a yellow solid.MS-ESI: 276 (M+1).

Step 6: 3,5,6,7-Tetrahydro-2H-indeno[5,6-b]furan-4-amine

Into a 50-mL round-bottom flask, was placed tert-butylN-[2H,3H,5H,6H,7H-indeno[5,6-b]furan-4-yl]carbamate (80 mg, 0.29 mmol)in DCM (8 mL) and TFA (3.0 mL, 0.030 mmol). The resulting solution wasstirred for 2 h at room temperature. The resulting mixture wasconcentrated. The residue was dissolved in 15 mL of DCM. The resultingmixture was washed with 2×15 ml of NaOH (aq.). The organic layer wasdried with Na₂SO₄ and then concentrated. This resulted in 50 mg (98.2%)of the title compound as a yellow solid. MS-ESI: 176 (M+1).

Tricyclo[6.2.0.0^(3,6)]deca-1,3(6),7-trien-2-amine Step 1:2,2′-(1,4-Phenylene)bis(ethan-1-ol)

Into a 1.0-L round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was placed 2-[4-(carboxymethyl)phenyl]aceticacid (40 g, 200 mmol) in THF (500 mL). This was followed by the additionof BH₃-Me₂S (60 mL, 600 mmol, 10 M) dropwise with stirring at 0° C. Theresulting solution was stirred for 24 h at RT. The reaction was thenquenched by the addition of 200 mL of water. The resulting solution wasextracted with 2×150 mL of ethyl acetate. The organic layers combinedand dried over anhydrous Na₂SO₄, then concentrated. The residue waseluted from a silica gel column with ethyl acetate/petroleum ether (1:10to 1:3). This resulted in 28 g (81.8%) of the title compound as brownoil. MS-ESI: 167 (M+1).

Step 2: 1,4-Bis(2-bromoethyl)benzene

Into a 50-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was placed2-[4-(2-hydroxyethyl)phenyl]ethan-1-ol (28 g, 168 mmol) in aq. HBr (300mL, 40% wt.). The resulting solution was stirred for 5 h at 100° C. inan oil bath. The resulting solution was diluted with 500 mL of water.The resulting solution was extracted with 3×200 mL of DCM. The organiclayers combined, then concentrated. This resulted in 40 g (81.4%) of thetitle compound as a white solid. MS-ESI: 291, 293, 295 (M+1).

Step 3: 1,4-Dibromo-2,5-bis(2-bromoethyl)benzene

Into a 500-mL round-bottom flask, was placed1,4-bis(2-bromoethyl)benzene (30 g, 103 mmol) in trichloromethane (200mL). To the above solution was added 12 (0.78 g, 3.08 mmol), iron powder(0.75 g, 13.4 mmol), Br₂ (41 g, 257 mmol). The resulting solution wasstirred for 24 h at RT. The reaction was then quenched by the additionof aqueous Na₂SO₃. The resulting solution was extracted with 3×200 mLDCM and the organic layers was combined and dried over anhydrous Na₂SO₄then concentrated. This resulted in 40 g (86.6%) of the title compoundas a white solid. MS-ESI: 449/451/453 (M+1).

Step 4: Tricyclo[6.2.0.0^(3,6)]deca-1,3(6),7-triene

Into a 1000-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was placed1,4-dibromo-2,5-bis(2-bromoethyl)benzene (40 g, 88.9 mmol) in THF (400mL). This was followed by the addition of n-BuLi (74.7 mL, 187 mmol, 2.5M) dropwise with stirring at −78° C. in a liquid nitrogen bath. Theresulting solution was stirred for 30 min at −78° C. The reaction wasthen quenched by the addition of aqueous NH₄Cl (300 ml) and extractedwith 2×200 mL of DCMDCM and the organic layers was combined and driedover anhydrous Na₂SO₄ then concentrated. This resulted in 8.0 g (69.1%)of the title compound as a light yellow solid.

Step 5: 2-Iodotricyclo[6.2.0.0^(3,6)]deca-1,3(6),7-triene

Into a 250-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was placedtricyclo[6.2.0.0^(3,6)]deca-1,3(6),7-triene (8 g, 61.45 mmol) in aceticacid (50 mL) and NIS (20.7 g, 92.2 mmol). The resulting solution wasstirred for 3 h at 50° C. in an oil bath. The resulting solution wasdiluted with 100 mL of water. The reaction was then quenched by theaddition of aqueous Na₂SO₃. The resulting solution was extracted with3×50 mL of DCM and the organic layers was combined and dried overanhydrous Na₂SO₄ then concentrated. The residue was eluted from a silicagel column with ethyl acetate/petroleum ether (1:100). This resulted in2.5 g (18.2%) of the title compound as a white solid.

Step 6: Tert-butyltricyclo[6.2.0.0^(3,6)]deca-1,3(6),7-trien-2-ylcarbamate

Into a 250-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was placed2-iodotricyclo[6.2.0.0^(3,6)]deca-1,3(6),7-triene (2.5 g, 9.76 mmol) intoluene (50 mL). To the stirred solution was added tert-butyl carbamate(3.43 g, 29.3 mmol), Pd₂(dba)₃ (447 mg, 0.49 mmol), Xphos (466 mg, 0.98mmol), and t-BuOK (3.29 g, 29.3 mmol). The resulting solution wasstirred for 14 h at 100° C. in an oil bath. The resulting mixture wasconcentrated. The residue was eluted from a silica gel column with ethylacetate/petroleum ether (1:50 to 1:30). This resulted in 1.5 g (62.6%)of the title compound as a light yellow solid. MS-ESI: 246 (M+1).

Step 7: Tricyclo[6.2.0.0^(3,6)]deca-1,3(6),7-trien-2-amine

Into a 50-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was placed tert-butylN-[tricyclo[6.2.0.0^(3,6)]deca-1,3(6),7-trien-2-yl]carbamate (1.5 g, 6.1mmol) in DCM (20 mL) and 2,2,2-trifluoroacetic acid (4.0 mL). Theresulting solution was stirred for 2 h at RT. The resulting mixture wasconcentrated. This resulted in 800 mg (90.1%) of the title compound as abrown solid. MS-ESI: 146 (M+1).

3-Amino-2,4-diisopropylbenzonitrile Step 1:3-Amino-2,4-dibromo-6-chlorobenzonitrile

Into a 500-mL round-bottom flask, was placed5-amino-2-chlorobenzonitrile (10 g, 65.8 mmol), ACN (200 mL) and NBS(17.6 g, 98.7 mmol). The resulting solution was stirred for 14 h at RT.The resulting mixture was concentrated. The residue was eluted from asilica gel column with ethyl acetate/petroleum ether (1:15 to 1:5). Thisresulted in 18 g of the title compound as a yellow solid. MS-ESI: 310,312 (M+1).

Step 2: 3-Amino-6-chloro-2,4-di(prop-1-en-2-yl)benzonitrile

Into a 500-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was placed3-amino-2,4-dibromo-6-chlorobenzonitrile (15 g, 48 mmol) in dioxane (200mL) and H₂O (20 mL),2-(tetramethyl-1,3,2-dioxaborolan-2-yl)prop-2-en-1-ylium (17.6 g, 106mmol), Cs₂CO₃ (47 g, 144 mmol), and Pd(dppf)C₁₂ (1.5 g, 4.8 mmol). Theresulting solution was stirred for 14 h at 100° C. in an oil bath. Theresulting mixture was concentrated. The residue was eluted from a silicagel column with ethyl acetate/petroleum ether (1:0 to 1:25). Thisresulted in 10 g of the title compound as brown oil. MS-ESI: 233 (M+1).

Step 3: 3-Amino-2,4-diisopropylbenzonitrile

Into a 500-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was placed3-amino-6-chloro-2,4-bis(prop-1-en-2-yl)benzonitrile (10 g, 43 mmol) inMeOH (50 mL). Then Pd/C (10% wt., 2.0 g) was added. The flask wasevacuated and flushed three times with hydrogen. The resulting solutionwas stirred for 16 h at RT under an atmosphere of hydrogen. The solidswere filtered out. The resulting filtrate was concentrated under vacuum.This resulted in 8.0 g of the title compound as brown oil. MS-ESI: 203(M+1).

8-Amino-1,2,3,5,6,7-hexahydro-s-indacen-1-ol Step 1:8-Amino-3,5,6,7-tetrahydro-s-indacen-1(2H)-one

Into a 250-mL round-bottom flask purged and maintained with an inertatmosphere of hydrogen, was placed a solution of8-nitro-1,2,3,5,6,7-hexahydro-s-indacen-1-one (700 mg, 3.22 mmol) inMeOH (10 mL), and Pd/C (10% wt., 100 mg). The flask was evacuated andflushed three times with hydrogen. The resulting solution was stirredfor 2 h at RT under an atmosphere of hydrogen. The Pd/C catalysts werefiltered out, and the filtrate was concentrated under vacuum. Thisresulted in 550 mg (91.2%) of the title compound as a yellow oil.MS-ESI: 188 (M+1).

Step 2: 8-Amino-1,2,3,5,6,7-hexahydro-s-indacen-1-ol

Into a 100 mL round-bottom flask, was placed a solution of8-amino-3,5,6,7-tetrahydro-s-indacen-1 (2H)-one (2.0 g, 10.7 mmol) inethanol. To this solution was added NaBH₄(1.9 g, 50 mmol) with stirringin portions at 0° C. in an ice bath. The resulting solution was stirredfor 16 h at RT. The reaction was quenched by water (10 mL). Theresulting solution was extracted with 3×50 mL of ethyl acetate and theorganic layers combined and dried over anhydrous sodium sulfate, andthen concentrated under vacuum. This resulted in 1.5 g of the titlecompound as a yellow solid. MS-ESI: 189 (M+1).

4-Amino-1,2,3,5,6,7-hexahydro-s-indacen-1-ol Step 1:4-Amino-3,5,6,7-tetrahydro-s-indacen-1(2H)-one

Into a 250-mL round-bottom flask purged and maintained with an inertatmosphere of hydrogen, was placed a solution of4-nitro-1,2,3,5,6,7-hexahydro-s-indacen-1-one (3.0 g, 13.8 mmol) in MeOH(30 mL), and Pd/C (10% wt., 500 mg). The flask was evacuated and flushedthree times with hydrogen. The resulting solution was stirred for 4 h atRT under an atmosphere of hydrogen. The Pd/C catalysts were filteredout, the filtrate was concentrated under vacuum. The residue was elutedfrom a silica gel column with DCM/MeOH (10:1). This resulted in 2.2 g(85.1%) of the title compound as a white solid. MS-ESI: 187 (M+1).

Step 2: 4-Amino-1,2,3,5,6,7-hexahydro-s-indacen-1-ol

Into a 100-mL round-bottom flask, was placed a solution of8-amino-3,5,6,7-tetrahydro-s-indacen-1(2H)-one (2.0 g, 10.7 mmol) inethanol (20 mL) and NaBH₄ (1.9 g, 50 mmol). The resulting solution wasstirred for 16 h at RT. The reaction was quenched with water. Theresulting solution was extracted with 3×50 mL of ethyl acetate and theorganic layers combined and dried over anhydrous sodium sulfate. Themixture was concentrated under vacuum. This resulted in 1.36 g of thetitle compound as a yellow solid. MS-ESI: 190 (M+1).

3-(3-(But-3-ynyl)-3H-diazirin-3-yl)propanoic acid Step 1: Methyl3-oxohept-6-ynoate

Into a 2000-mL 3-neck round-bottom flask purged with and maintainedunder nitrogen, was placed methyl 3-oxobutanoate (20 g, 172 mmol) in THF(200 mL). To the above solution was added LDA (200 mL, 400 mmol, 2 M)dropwise at −20° C. in a dry ice bath. Then reaction was allowed toreact at −20° C. for 30 min. Then 3-bromoprop-1-yne (20.5 g, 172 mmol)was added to the reaction solution in portions at −20° C. The resultingsolution was stirred for 3 h at −20° C. in a dry ice bath. The reactionwas then quenched by the addition of 500 mL of NH₄Cl solution. The pHvalue of the solution was adjusted to 3 with HCl (aq). The resultingsolution was extracted with 3×200 ml of ethyl acetate and the organiclayers was combined and dried over anhydrous Na₂SO₄, then concentrated.This resulted in the title compound (2.0 g, 7.53%) as white oil.

Step 2: Methyl 2-(2-(but-3-ynyl)-1,3-dioxolan-2-yl)acetate

Into a 500-mL round-bottom flask, was placed methyl 3-oxohept-6-ynoate(20 g, 130 mmol) in toluene (200 mL), ethane-1,2-diol (40.2 g, 649 mmol)and TsOH (2.23 g, 13 mmol). The resulting solution was stirred for 6 hat 120° C. in an oil bath. The resulting solution was diluted with 200mL of Et₂O. The resulting mixture was washed with 3×100 ml of NaHCO₃ and3×100 ml of saturated NaCl solution. The mixture was dried overanhydrous sodium sulfate and concentrated. This resulted in the titlecompound (20 g, 77.9%) as yellow oil.

Step 3: 2-(2-(But-3-ynyl)-1,3-dioxolan-2-yl)ethanol

Into a 1.0-L 3-necked round-bottom flask purged and maintained with aninert atmosphere of nitrogen, was placed methyl2-[2-(but-3-yn-1-yl)-1,3-dioxolan-2-yl]acetate (90 g, 454 mmol) in THF(300 mL). To this above solution was added LiAlH₄ (17.9 g, 472 mmol) inportions with stirring at 0° C. in an ice/ethanol bath. The resultingsolution was stirred for 6 h at RT. The reaction was then quenched bythe addition of water/ice. The solids were filtered out. The resultingfiltrate was concentrated under vacuum. This resulted in the titlecompound (80 g crude) and used in the next step directly. MS-ESI: 169(M−1).

Step 4: 1-Hydroxyhept-6-yn-3-one

Into a 3.0-L 3-necked round-bottom flask purged and maintained with aninert atmosphere of nitrogen, was placed2-[2-(but-3-yn-1-yl)-1,3-dioxolan-2-yl]ethan-1-ol (80 g, 470 mmol) inTHF (1.0 L) and HCl (500 mL). The resulting solution was stirred for 16h at RT. The resulting solution was diluted with 1.0 L of water. Themixture was extracted with 3×1.0 L of ethyl acetate and the organiclayer was combined and dried over anhydrous sodium sulfate. The solidswere filtered out. The resulting filtrate was concentrated under vacuum.The residue was eluted from a silica gel column with DCM/petroleum ether(1:1). This resulted in 20 g of the title compound as a white solid.MS-ESI: 125 (M−1).

Step 5: 2-(3-(But-3-ynyl)diaziridin-3-yl)ethanol

Into a 500-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was placed 1-hydroxyhept-6-yn-3-one (20 g, 159mmol) in DCM (250 mL). To the above solution was introduced NH₃ (g) for15 min at −40° C. in a liquid nitrogen/ethanol bath. The resultingsolution was stirred for 1 h at −40° C. and then allowed to react for 16h at RT. The resulting mixture was concentrated. This resulted in 18 g(crude) of the title compound as a white solid. MS-ESI: 141 (M+1).

Step 6: 2-(3-(But-3-ynyl)-3H-diazirin-3-yl)ethanol

Into a 500-mL 3-necked round-bottom flask purged and maintained with aninert atmosphere of nitrogen, was placed2-[3-(but-3-yn-1-yl)diaziridin-3-yl]ethan-1-ol (14.4 g, 114 mmol) in DCM(200 mL), TEA (34.6 g, 342 mmol), 12 (58 g, 228 mmol). The resultingsolution was stirred for 4 h at RT. The reaction was then quenched bythe addition of Na₂S₂O₃. The resulting mixture was quenched with 100 mLof water. The resulting solution was extracted with 3×300 mL of DCM andthe organic layers combined and dried over anhydrous sodium sulfate. Thesolids were filtered out. The resulting mixture was concentrated. Thisresulted in 6.0 g (38%) of the title compound as a white solid. MS-ESI:139 (M+1).

Step 7: 3-(But-3-ynyl)-3-(2-iodoethyl)-3H-diazirine

Into a 250-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was placed2-[3-(but-3-yn-1-yl)-3H-diazirin-3-yl]ethan-1-ol (5.0 g, 36.2 mmol) inTHF (20 mL), imidazole (3.7 g, 54.3 mmol), 12 (9.18 g, 36.2 mmol), PPh₃(14.2 g, 54.3 mmol). The resulting solution was stirred for 16 h at RT.The reaction was then quenched by the addition of 20 mL of saturatedNa₂S₂O₃ solution. The resulting solution was extracted with 3×50 mL ofDCM dried over anhydrous sodium sulfate. The solids were filtered out.The resulting mixture was concentrated. This resulted in 5.0 g (crude)of the title compound as a yellow solid. MS-ESI: 248 (M+1).

Step 8: 3-(3-(But-3-ynyl)-3H-diazirin-3-yl)propanenitrile

Into a 500-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was placed3-(but-3-yn-1-yl)-3-(2-iodoethyl)-3H-diazirine (5.0 g, 20.2 mmol) in DMF(250 mL), KCN (2.62 g, 40.3 mmol). The resulting solution was stirredfor 16 h at 60° C. in an oil bath. The reaction was then quenched by theaddition of 20 mL of FeSO₄ solution. The resulting solution wasextracted with 3×50 ml of ethyl acetate dried over anhydrous sodiumsulfate. The solids were filtered out. The resulting mixture wasconcentrated. This resulted in 2.0 g (crude) of the title compound as asolid. MS-ESI: 148 (M+1).

Step 9: 3-(3-(But-3-ynyl)-3H-diazirin-3-yl)propanoic acid

Into a 100-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was placed3-[3-(but-3-yn-1-yl)-3H-diazirin-3-yl]propanenitrile (1.0 g, 3.40 mmol)in MeOH (40 mL), NaOH (272 mg, 6.79 mmol). The resulting solution wasstirred for 16 h at 90° C. in an oil bath. The resulting solution wasconcentrated. The residue was eluted from a silica gel column with ethylacetate/petroleum ether (1:1). This resulted in 400 mg crude (26.6%) ofthe title compound as yellow oil. MS-ESI: 167 (M+1).

3,5-Diisopropyl-1-phenyl-1H-pyrazol-4-amine Step 1:3,5-Diisopropyl-1-phenyl-1H-pyrazole

Into a 100-mL round-bottom flask, was placed 2-propanol (50 mL),phenylhydrazine (3.81 g, 35.2 mmol) and 2,6-dimethylheptane-3,5-dione(5.0 g, 32.0 mmol). The resulting solution was stirred overnight at 85°C. in an oil bath. The resulting mixture was concentrated. The residuewas dissolved in 100 mL of ethyl acetate. The resulting mixture waswashed with 50 mL of H₂O. The mixture was dried over anhydrous sodiumsulfate and then concentrated. This resulted in 6.9 g (94%) of the titlecompound as a light yellow oil. MS-ESI: 229 (M+1).

Step 2: 3,5-Diisopropyl-4-nitro-1-phenyl-1H-pyrazole

Into a 100-mL round-bottom flask, was placed1-phenyl-3,5-bis(propan-2-yl)-1H-pyrazole (6.9 g, 30 mmol) in AC₂O (50mL). This was followed by the addition of HNO₃ (4.07 mL, 91 mmol)dropwise with stirring at 0° C. in 10 min. The resulting solution wasstirred for overnight at RT. The residue was dissolved in 150 mL ofethyl acetate. The resulting mixture was washed with 2×100 mL of H₂O.The mixture was dried over anhydrous sodium sulfate and thenconcentrated. This resulted in 3.7 g (44.8%) of the title compound asyellow oil. MS-ESI: 274 (M+1).

Step 3: 3,5-Diisopropyl-1-phenyl-1H-pyrazol-4-amine

Into a 250-mL round-bottom flask, was placed4-nitro-1-phenyl-3,5-bis(propan-2-yl)-1H-pyrazole (3.7 g, 13.5 mmol) inMeOH (100 mL), to the stirred solution was added Pd/C (10% wt., 400 mg).The flask was evacuated and flushed three times with hydrogen. Theresulting solution was stirred overnight at RT under an atmosphere ofhydrogen. The Pd/C catalysts were filtered out, the filtrate wasconcentrated under vacuum. This resulted in 2.7 g (82%) of the titlecompound as a light yellow oil. MS-ESI: 244 (M+1).

1,2,3,6,7,8-Hexahydro-as-indacen-4-amine Step 1:4-Nitro-1,6,7,8-tetrahydro-as-indacen-3(2H)-one (308) and5-nitro-1,6,7,8-tetrahydro-as-indacen-3(2H)-one (309″)

Into a 250-mL round-bottom flask was placed a solution of1,6,7,8-tetrahydro-as-indacen-3(2H)-one (Cpd 307″ was isolated from 113″in Scheme 23 by chromatography) (9.8 g, 46.5 mmol) in H₂SO₄ (50 mL).Then HNO₃ (5.85 g, 92.9 mmol) was added dropwise over 10 min at 0° C.The resulting solution was stirred for 1 h at 0° C. The reaction mixturewas slowly added to a mixture of water/ice (100 mL) and DCM (50 mL) withice bath cooling. The organic layer was collected, dried over Na₂SO₄ andconcentrated under vacuum. This resulted in 11 g (89%) of a mixture ofcpd 308″ and cpd 309″ as a yellow solid. The mixture was monitored byTLC (ethyl acetate/petroleum ether=1/10, R_(f)=0.4),

Step 2: 1,2,3,6,7,8-hexahydro-as-indacen-4-amine (116)

Into a 100-mL round-bottom flask was placed a solution of the mixture of4-nitro-1,6,7,8-tetrahydro-as-indacen-3(2H)-one and5-nitro-1,6,7,8-tetrahydro-as-indacen-3 (2H)-one (2.17 g, 10 mmol) inMeOH (30 mL). To the solution was added MSA (1.15 g, 12 mmol). ThenPd(OH)₂/C (20% wt., 550 mg) was added. The flask was evacuated andfilled three times with hydrogen. The resulting mixture was stirred for16 h at RT under hydrogen (50 psi). The solids were filtered out andwashed with MeOH. The MeOH filtrate and wash was diluted with water (50mL) and the pH was adjusted to 10.6 with 2 N NaOH. The resulting mixturewas filtered and the crude solids were recrystallized from MeOH/water(9:1) with heating. This resulted in 1.38 g (80%) of the title compoundas an off-white solid. MS-ESI: 174 (M+1).

Intermediate 117A Intermediate 117

1,2,3,5,6,7-Hexahydro-s-indacen-3,3,5,5-d₄-4-amine Step 1:5-Bromo-2,3-dihydro-1H-indene-1,1-d₂

Into a 250-mL 3-necked round-bottom flask purged and maintained with aninert atmosphere of nitrogen, was placed a solution of LiAlD₄(1.57 g, 37mmol) in Et₂O (150 mL). This was followed by the addition of AlCl₃ (10.1g, 76 mmol) in portions at 0° C. in 5 min. To this was added5-bromo-2,3-dihydro-1H-inden-1-one (4.0 g, 19 mmol) in portions at 0° C.in 5 min. The resulting solution was stirred for 4 h at RT. The reactionmixture was cooled to 0° C. with a water/ice bath. The reaction was thenquenched by careful addition of 10 mL of water. The solids were filteredout. The resulting solution was extracted with 3×100 mL of ethyl acetateand concentrated under vacuum. This resulted in 3.5 g (93%) of the titlecompound as brown oil. MS-ESI: 199/201 (M+1).

Step 2: Tert-butyl (E)-3-(2,3-dihydro-1H-inden-5-yl-1,1-d₂)acrylate

Into a 250-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was placed a solution of5-bromo-2,3-dihydro-1H-indene-1,1-d₂ (7.0 g, 35 mmol) in DMF (80 mL), tothe stirred solution was added tris(4-methylphenyl)phosphane (1.07 g,3.52 mmol), tert-butyl prop-2-enoate (4.0 mL), triethylamine (5.0 mL)and Pd(OAc)₂ (395 mg, 1.76 mmol). The resulting solution was stirredovernight at 100° C. in an oil bath. The resulting mixture wasconcentrated under vacuum. The resulting solution was extracted with3×50 mL of ethyl acetate and the organic layers combined and dried overanhydrous sodium sulfate. The residue was eluted from a silica gelcolumn with DCM/petroleum ether (1:1). This resulted in 5.7 g (66%) ofthe title compound as light yellow oil. MS-ESI: 247 (M+1).

Step 3: Tert-butyl 3-(2,3-dihydro-1H-inden-5-yl-1,1-d₂)propanoate

Into a 100-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was placed a solution of tert-butyl(E)-3-(2,3-dihydro-1H-inden-5-yl-1,1-th)acrylate (5.8 g, 24 mmol) inMeOH (40 mL), to the stirred solution was added Pd/C (580 mg, 10% wt.).The flask was evacuated and flushed three times with hydrogen. Theresulting solution was stirred for 1 h at RT under an atmosphere ofhydrogen. The Pd/C catalysts were filtered out, the filtrate wasconcentrated under vacuum. This resulted in 5.7 g (98%) of the titlecompound as colorless oil. MS-ESI: 249 (M+1).

Step 4: 3-(2,3-Dihydro-1H-inden-5-yl-1,1-d₂)propanoic acid

Into a 100-mL round-bottom flask, was placed a solution of tert-butyl3-(2,3-dihydro-1H-inden-5-yl-1,1-d₂)propanoate (4.3 g, 17.3 mmol) in DCM(50 mL), to the stirred solution was added CF₃COOH (5.5 mL, 74 mmol).The resulting solution was stirred for overnight at RT. The resultingmixture was concentrated under vacuum. This resulted in 3.1 g (93%) ofthe title compound as an off-white solid. MS-ESI: 191 (M−1).

Step 5: 3-(2,3-Dihydro-1H-inden-5-yl-1,1-d₂)propanoyl chloride

Into a 100-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was placed a solution of3-(2,3-dihydro-1H-inden-5-yl-1,1-th)propanoic acid (9.0 g, 41.7 mmol) inDCM (40 mL). This was followed by the addition of oxalic dichloride (8.0mL) at 0° C. To this was added DMF (0.5 mL) at 0° C. The resultingsolution was stirred for 3 h at RT. The resulting mixture wasconcentrated under vacuum. This resulted in 4.0 g (41%) of the titlecompound as brown oil.

Step 6: 3,5,6,7-Tetrahydro-s-indacen-1(2H)-one-7,7-d₂

Into a 100-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was placed a solution of3-(2,3-dihydro-1H-inden-5-yl-1,1-d₂)propanoyl chloride (3.9 g, 18 mmol)in DCE (40 mL). This was followed by the addition of AlCl₃ (3.3 g, 25mmol) in portions at 0° C. in 2 min. The resulting solution was stirredfor 1 h at RT. The reaction was then quenched by the addition of 200 mLof water/ice. The resulting solution was extracted with 3×50 mL of DCMand the organic layers combined and dried over anhydrous sodium sulfate.The residue was eluted from a silica gel column with ethylacetate/petroleum ether (2:100). This resulted in 1.5 g (46%) of thetitle compound as an off-white solid. MS-ESI: 175 (M+1).

Step 7: 8-Nitro-3,5,6,7-tetrahydro-s-indacen-1(2H)-one-7,7-d₂ (Cpd 318″,major) and 4-Nitro-3,5,6,7-tetrahydro-s-indacen-1(2H)-one-7,7-d₂ (Cpd317″, minor)

Into a 25-mL round-bottom flask, was placed3,5,6,7-tetrahydro-s-indacen-1(2H)-one-7,7-d₂ (120 g). This was followedby the addition of H₂SO₄ (8.0 mL) at 0° C. To this was added HNO₃ (2.0mL) at 0° C. in 2 min. To the mixture was added H₂SO₄ (2.0 mL) at 0° C.in 2 min. The resulting solution was stirred for 1 h at 0° C. Thereaction was then quenched by the addition of water/ice. The resultingsolution was extracted with 3×50 mL of ethyl acetate dried in an ovenunder reduced pressure. The residue was separated on silica gel elutedwith ethyl acetate/petroleum ether (3:100). This resulted in 870 mg ofcpd 318″ and 290 mg of cpd 317″, both as yellow solids. Cpd 317″: ¹H NMR(300 MHz, CDCl₃) δ 7.83 (s, 1H), 3.55-3.45 (m, 2H), 3.42 (t, J=7.6 Hz,2H), 2.84-2.74 (m, 2H), 2.22 (t, J=7.6 Hz, 2H). Cpd 318″: ¹H NMR (300MHz, CDCl₃) δ 7.46 (s, 1H), 3.20 3.00 (m, 4H), 2.83-2.73 (m, 2H), 2.20(t, J=7.5 Hz, 2H).

Step 8: 8-Amino-3,5,6,7-tetrahydro-s-indacen-1(2H)-one-7,7-d₂

Into a 250-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was placed a solution of8-nitro-3,5,6,7-tetrahydro-s-indacen-1(2H)-one-7,7-d₂ (870 mg) in MeOH(100 mL), to the stirred solution was added Pd/C (87 mg, 10% wt.). Theflask was evacuated and flushed three times with hydrogen. The resultingsolution was stirred for 1 h at RT under an atmosphere of hydrogen. ThePd/C catalysts were filtered out, the filtrate was concentrated undervacuum. This resulted in 700 mg of the title compound as a yellow solid.MS-ESI: 190 (M+1).

Step 9: 1,2,3,5,6,7-Hexahydro-s-indacen-3,3,5,5-d₄-4-amine

Into a 250-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was placed a solution of LiAlD₄ (160 mg, 3.8mmol) in Et₂O (40 mL). This was followed by the addition of AlCl₃ (634mg, 4.8 mmol) in portions at 0° C. in 2 min. To this solution was added8-amino-3,5,6,7-tetrahydro-s-indacen-1(2H)-one-7,7-d₂ (600 mg, 3.17mmol) at 0° C. The resulting solution was stirred for 4 h at RT. Thereaction was then quenched by the addition of 10 mL of water. Theresulting solution was diluted with 20 mL of EtOAc. The solids werefiltered out. The resulting solution was extracted with 3×50 mL of ethylacetate dried over anhydrous sodium sulfate and concentrated undervacuum. The residue was eluted from a silica gel column with ethylacetate/petroleum ether (5:1). This resulted in 470 mg (78%) of theIntermediate 117 as a yellow solid. MS-ESI: 178 (M+1).

1,2,3,5,6,7-hexahydro-s-indacen-1,1,7,7-d₄-4-amine

Intermediate 117A was prepared starting from compound 317″ and using thesame procedure as shown in scheme 73 above for converting compound 318″to intermediate 117. MS-ESI: 178 (M+1).

TABLE 15 The Intermediates in the following Table were prepared usingsimilar procedure as shown in Scheme 30 above for converting compound130″ to Intermediate 44. Intermediate # Structure IUPAC NameIntermediate 118″

6-Ethyl-7-isocyanato- 1H-indazole Intermediate 119″

6-Ethyl-7-isocyanato-1- methyl-1H-indazole Intermediate 120″

3-Isocyanato-2,4,5,6- tetrahydro-1H- cyclobuta[f]indene Intermediate121″

4-Isocyanato-3,5,6,7- tetrahydro- 2H-indeno[5,6- b]furan Intermediate122″

2-Isocyanato- tricyclo[6.2.0.03,6]deca- 1,3(6),7-triene Intermediate123″

8-Isocyanato-2,3,6,7- tetrahydros-indacen- 1(5H)-one Intermediate 124″

4-Isocyanato-2,3,6,7- tetrahydros-indacen- 1(5H)-one Intermediate 125″

4-isocyanato- 1,2,3,5,6,7-hexahydro- s-indacene-3,3,5,5-d₄ Intermediate126″

4-isocyanato- 1,2,3,5,6,7-hexahydro- s-indacene-1,1,7,7-d₄

Schemes below the synthesis of sulfonimidamide Intermediates 118-123.

N-(tert-butyldimethylsilyl)-6-isopropylpyridine-3-sulfonimidamide

Steps 1-4 used similar procedures for converting compound 245″ toIntermediate 88 shown in Scheme 56 to afford Intermediate 118 fromcompound 322″. MS-ESI: 314 (M+1).

Step 1: 4-Amino-3-fluoro-N-methylbenzamide

Into a 500 mL round-bottom flask were added 4-amino-3-fluorobenzoic acid(15 g, 97 mmol) and DMF (100 mL) at RT. To the stirred solution wasadded HATU (74 mg, 0.19 mmol) and DIEA (25 mg, 0.19 mmol) at 0° C. Tothe above mixture was added MeNH₂/THF (2M, 97 mL, 194 mmol) in oneportion at 0° C. The resulting mixture was stirred for additional 2 h atRT. The resulting mixture was extracted with EtOAc (3×100 mL). Thecombined organic layers were dried over anhydrous Na₂SO₄. Afterfiltration, the filtrate was concentrated under reduced pressure. Theresidue was eluted from silica gel column with petroleum ether/EtOAc(1:1) to afford the title compound (16 g, 98%) as yellow oil. MS-ESI:169 (M+1).

Steps 2-3 used similar procedures for converting compound 27 toIntermediate 29 shown in Scheme 9 to afford compound 329″ from compound327″. MS-ESI: 233 (M+1).

Step 4: 2-Fluoro-4-((methylamino)methyl)benzenesulfonamide

Into a 250-mL round-bottom flask were placed3-fluoro-N-methyl-4-sulfamoylbenzamide (1.2 g) in THF (40 mL) at 0° C.To the stirred solution was added LiAlH₄ (543 mg, 14 mmol) in portionsat 0° C. under nitrogen atmosphere. The resulting mixture was stirredovernight at 70° C. The reaction was quenched with water (2 mL). Theresulting mixture was filtered, the filter cake was washed with EtOAc(3×10 mL). The filtrate was concentrated under reduced pressure. Theresidue was purified by Prep-TLC (EtOAc/MeOH=25:1) to afford the titlecompound (800 mg, 77%) as a white solid. MS-ESI: 219 (M+1).

Step 5: Tert-butyl (3-fluoro-4-sulfamoylbenzyl)(methyl)carbamate

Into a 100-mL round-bottom flask were placed2-fluoro-4-[(methylamino)methyl]benzene-1-sulfonamide (800 mg, 3.7 mmol)in THF (20 mL) at 0° C. To a stirred solution was added (Boc)₂O (1.5 g,6.89 mmol) in portions at 0° C. The resulting mixture was stirred for 2h at RT and concentrated under reduced pressure. The residue waspurified by Prep-TLC (PE/EtOAc 1:1) to afford the title compound (900mg, 77%) as a white solid. MS-ESI: 319 (M+1).

Steps 6-7 used similar procedures for converting compound 248″ toIntermediate 88 shown in Scheme 56 to afford Intermediate 119 fromcompound 331″. MS-ESI: 432 (M+1).

N′-(tert-butyldimethylsilyl)-4-((dimethylamino)methyl)-3-fluorobenzenesulfonimidamideStep 1: 1-(2-Fluoro-4-nitrophenyl)-N,N-dimethylmethanamine

Into a 250-mL round-bottom flask, was placed a solution of1-(bromomethyl)-2-fluoro-4-nitrobenzene (8.0 g, 34 mmol) in MeOH (50mL). This was followed by the addition of dimethylamine (2 M, 21 mL)dropwise with stirring at 0° C. in 5 min. The resulting solution wasstirred for 4 h at RT. The resulting mixture was concentrated undervacuum. This resulted in 7.0 g crude title compound as yellow oil.MS-ESI: 199 (M+1).

Step 2: 4-((Dimethylamino)methyl)-3-fluoroaniline

Into a 100-mL round-bottom flask, was placed the solution of[(2-fluoro-4-nitrophenyl)methyl]dimethylamine (7.0 g, 35 mmol) in AcOH(20 mL), to the stirred solution was added iron powder (10 g, 179 mmol).The resulting solution was stirred for 16 h at RT. The solids werefiltered out. The resulting filtrate was concentrated under vacuum. Theresidue was eluted from a silica gel column with DCM/MeOH (9:1). Thisresulted in 6.5 g crude title compound as yellow oil. MS-ESI: 169 (M+1).

Steps 3-4 used similar procedures for converting compound 145″ tocompound 147″ shown in Scheme 36 to afford compound 337″ from compound335″. MS-ESI: 233 (M+1).

Steps 5-6 used similar procedures for converting compound 148″ toIntermediate 59 shown in Scheme 36 to afford Intermediate 120 fromcompound 337″. MS-ESI: 233 (M+1).

N′-(tert-butyldimethylsilyl)-4-isopropylthiophene-2-sulfonimidamide

Steps 1-2 used similar procedures for converting compound 158″ tointermediate 61 shown in Scheme 38 to afford compound 341″ from compound339″. MS-ESI: 221 (M+1).

Step 3 used similar procedures for converting compound 147″ to compound148″ shown in Scheme 36 to afford compound 342″ from compound 341″.MS-ESI: 221 (M+1).

Step 4: 4-Isopropylthiophene-2-sulfonamide

Into a 250-mL round-bottom flask, was placed the solution of4-(2-hydroxypropan-2-yl)thiophene-2-sulfonamide (1.5 g, 6.79 mmol) inDCM (20 mL). To the stirred solution was added TFA (3.9 g, 34 mmol) andEt₃SiH (2.32 g, 20 mmol). The result solution was stirred overnight atRT. The mixture was concentrated under vacuum. The residue was elutedfrom silica gel column with a gradient of ethyl acetate/petroleum ether(1:5 to 1:3). This resulted in 1.1 g (79%) of the title compound as alight yellow solid. MS-ESI: 206 (M+1).

Steps 5-6 used similar procedures for converting compound 148″ toIntermediate 59 shown in Scheme 36 to afford Intermediate 121 fromcompound 344″. MS-ESI: 319 (M+1).

N-(tert-butyldimethylsilyl)-4-(1-methylpyrrolidin-2-yl)benzenesulfonimidamideStep 1: 2-(4-Bromophenyl)-1-methylpyrrolidine

Into a 100-mL round-bottom flask, was placed2-(4-bromophenyl)pyrrolidine (3.0 g, 13.3 mmol) in HCHO (3.23 g, 37%wt.), to the stirred solution was added NaBH₃CN (2.5 g, 40 mmol). Theresulting solution was stirred for 12 h at RT and concentrated undervacuum. The residue was eluted from a silica gel column with ethylacetate/petroleum ether (1:1). This resulted in 2.8 g (88%) of the titlecompound as a light yellow solid. MS-ESI: 240/242 (M+1).

Steps 2-6 used similar procedures for converting compound 245″ toIntermediate 88 shown in Scheme 56 to afford Intermediate 122″ fromcompound 347″. MS-ESI: 354 (M+1).

N-(tert-butyldimethylsilyl)-2-(2-methyl-1,3-dioxolan-2-yl)thiazole-5-sulfonimidamideStep 1: 2-(2-Methyl-1,3-dioxolan-2-yl)thiazole

Into a 50-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was placed 1-(1,3-thiazol-2-yl)ethan-1-one (27g, 212 mmol) in toluene (300 mL), to the stirred solution was added TsOH(2.0 g, 11.6 mmol) and ethane-1,2-diol (40 g, 644 mmol). The resultingsolution was stirred for 14 h at 110° C. in an oil bath. The resultingmixture was concentrated under vacuum. The residue was eluted from asilica gel column with ethyl acetate/petroleum ether (1:20 to 1:10).This resulted in 36 g (99%) of the title compound as brown oil. MS-ESI:172 (M+1).

Steps 2-5 used similar procedures for converting compound 245″ toIntermediate 88 shown in Scheme 56 to afford Intermediate 123 fromcompound 353″. MS-ESI: 363 (M+1).

Reagent 1 Dichlorotriphenylphosphorane

This reagent was either purchased or prepared using the followingprocedure:

An oven dried 40 mL vial equipped with a stir bar was capped with arubber septum and flushed with nitrogen. At room temperature, a solutionof PPh₃ (0.85 g, 3.2 mmol) in anhydrous 1,2-dichloroethane (5 mL) wasintroduced via syringe. The reaction vessel was immersed in an ice/waterbath and cooled for 5 min. A solution of hexachloroethane (0.76 g, 3.2mmol) in anhydrous 1,2-dichloroethane (5 mL) was introduced dropwise viasyringe. After the addition was complete the reaction mixture wasstirred at the same temperature for an additional 5 min and then placedinto a preheated block set at 80° C. Heating was continued for 4.5 h, atwhich time the reaction was assumed to be complete. The light goldenclear solution was cooled to ambient temperature. The reagent thusprepared was transferred via syringe in subsequent reactions without anywork up or purification. The total volume of the reaction mixture was 11mL for the molar calculations for next steps. This solution containingPPh₃Cl₂ was stored under nitrogen at room temperature until used.

Reagent 2 Polymer-bound dichlorotriphenylphosphorane

Polystyrene bound PPh₃ (0.32 g, 0.32 mmol) was suspended in anhydrousdichloroethane (6 mL) and shaked on a shaker for 5 mins. It was thenfiltered and the process was repeated again to swell the polymer.Filtered resin was suspended in anhydrous dichloroethane (6 mL) a thirdtime and the whole suspension was transferred into an oven dried 40 mLvial with a stir bar via pipette. The vial was capped with a rubberseptum and connected to a steady flow of nitrogen. The reaction vesselwas immersed in an ice/water bath and cooled down for 10 min. A solutionof hexachloroethane (0.076 g, 0.32 mmol) in anhydrous 1,2-dichloroethane(2 mL) was introduced drop wise via syringe. After the addition wascomplete the reaction mixture was placed in an already heated block setat 82° C. for 5 h. At this point the reaction is assumed to becompleted. It was gradually brought to room temperature and used in thenext step as is. This reagent was used at 1.5 equiv. with respect tosulfonamide in the next step.

SYNTHETIC EXAMPLES Example 1

Example 1 (181):N′-(1,2,3,5,6,7-hexahydro-s-indacen-4-ylcarbamoyl)-4-(2-hydroxypropan-2-yl)-5-methylfuran-2-sulfonimidamide

Example 1 was synthesized according to the general method shown inScheme 1, as illustrated below.

Examples 2 and 3

Examples 2 (181a) and 3 (181b): (S)- and(R)—N′-(1,2,3,5,6,7-hexahydro-s-indacen-4-ylcarbamoyl)-4-(2-hydroxypropan-2-yl)-5-methylfuran-2-sulfonimidamide

Examples 2 and 3 were prepared through chiral separation of Example 1 asillustrated below.

Step 1:N′-(tert-butyldimethylsilyl)-N-(1,2,3,5,6,7-hexahydro-s-indacen-4-ylcarbamoyl)-4-(2-hydroxypropan-2-yl)-5-methylfuran-2-sulfonimidamide

Into a 50-mL round-bottom flask was placedN′-(tert-butyldimethylsilyl)-4-(2-hydroxypropan-2-yl)-5-methylfuran-2-sulfonimidamide(200 mg, 0.6 mmol), THF (10 mL), NaH (60% wt, 48 mg, 1.2 mmol). This wasfollowed by the addition of a solution of4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (120 mg, 0.6 mmol) in THF(1 mL) dropwise with stirring at RT. The resulting solution was stirredfor 12 h at RT. The reaction was then quenched by the addition of 10 mLof NH₄Cl (sat.). The resulting solution was extracted with 3×10 mL ofDCM and the organic layers combined and concentrated under vacuum. Theresidue was applied onto a silica gel column and eluted with ethylacetate/petroleum ether (1:10 to 1:3). This resulted in 140 mg (43.8%)of the title compound as brown oil. MS-ESI: 532.0 (M−1).

Step 2:N′-(1,2,3,5,6,7-hexahydro-s-indacen-4-ylcarbamoyl)-4-(2-hydroxypropan-2-yl)-5-methylfuran-2-sulfonimidamide

Into a 50-mL round-bottom flask was placedN′-(tert-butyldimethylsilyl)-N-(1,2,3,5,6,7-hexahydro-s-indacen-4-ylcarbamoyl)-4-(2-hydroxypropan-2-yl)-5-methylfuran-2-sulfonimidamide(130 g, 0.2 mmol), THF (10 mL), and TBAF (300 mg, 0.5 mmol). Theresulting solution was stirred for 2 h at RT and then concentrated undervacuum. The crude product was purified by Prep-HPLC using method Eeluted with a gradient of 30˜60% ACN. This resulted in 82 mg (80.3%) ofExample 1 as a white solid.

Example 1

MS-ESI: 418.0 (M+1). ¹H NMR (400 MHz, DMSO-d₆) δ 8.39 (s, 1H), 7.57 (s,2H), 6.87 (s, 1H), 6.85 (s, 1H), 5.04 (s, 1H), 2.79 (t, J=7.4 Hz, 4H),2.71-2.63 (m, 4H), 2.42 (s, 3H), 1.94 (tt, J=7.4 and 7.4 Hz, 4H), 1.40(s, 6H).

Step 3: Chiral Separation

The product obtained as described in the previous step (70 mg) wasresolved by Chiral-Prep-HPLC using the following conditions: Column,ChiralPak ID, 2*25 cm, 5 um; mobile phase, Hex and EtOH (hold 20% EtOHover 18 min); Flow rate, 20 mL/min; Detector, UV 254/220 nm. Thisresulted in 26.8 mg of Example 2 (front peak, 99% ee) as a white solidand 27.7 mg (second peak, 99.3% ee) of Example 3 as a white solid.

Example 2

MS-ESI: 418.0 (M+1). ¹H NMR (400 MHz, DMSO-d₆) δ 8.36 (s, 1H), 7.57 (s,2H), 6.87 (s, 1H), 6.85 (s, 1H), 5.03 (s, 1H), 2.78 (t, J=7.2 Hz, 4H),2.73-2.60 (m, 4H), 2.41 (s, 3H), 1.93 (tt, J=7.2 and 7.2 Hz, 4H), 1.39(s, 6H).

Example 3

MS-ESI: 418.0 (M+1). ¹H NMR (400 MHz, DMSO-d₆) δ 8.39 (s, 1H), 7.58 (s,2H), 6.87 (s, 1H), 6.85 (s, 1H), 5.03 (s, 1H), 2.78 (t, J=7.2 Hz, 4H),2.73-2.60 (m, 4H), 2.41 (s, 3H), 1.93 (tt, J=7.2 and 7.2 Hz, 4H), 1.39(s, 6H).

Single crystal X-ray crystallographic analysis was performed on compound181a. FIG. 1 shows ball and stick models of the asymmetrical unitcontaining two crystallographically independent molecules of compound181a, with hydrogen atoms omitted for clarity. Table M below showsfractional atomic coordinates of compound 181a.

TABLE M Fractional Atomic Coordinates (×10⁴) and Equivalent IsotropicDisplacement Parameters (Å² × 10³) for Example 2. U_(eq) is defined as ⅓of the trace of the orthogonalised U_(IJ) tensor. Atom x y z U(eq) S1722.5(7)  5368.3(5)  6903.3(4)  14.52(18) S2 4304.8(7)  505.4(5) 3262.9(4)  16.15(18) O1 2143(2) 6680.8(16)  8220.2(13)  16.1(4) O2−195(2) 4624.4(17)  6478.0(14)  21.9(5) O5 2874(2) 1624.4(17) 1805.2(15)  22.8(5) O6 5238(2) −141.6(18)  3795.4(15)  25.6(5) O31492(3) 5769.7(18)  5397.8(14)  25.5(5) O7 2974(2) 2151.0(17) 3638.1(14)  24.6(5) N1  51(2) 7218.5(19)  8513.8(16)  14.6(5) N2  59(3)5986.0(18)  7536.5(16)  15.3(5) O4 2422(3) 8513(2) 4297.8(17)  34.3(6)N4 4956(2) 2247(2) 1576.1(16)  16.9(5) O8 2771(3) 3430(2) 6070.3(18) 36.7(6) N5 4980(3) 1071.7(19)  2602.6(17)  16.6(5) N3 2120(3) 4817(2)7347.5(17)  16.3(5) C13  854(3) 6633(2) 8105.0(18)  12.9(6) C1  605(3)7947(2) 9133.7(19)  14.4(6) N6 2978(3) −121(2) 2801.8(19)  20.2(6) C224388(3) 2952(2)  936.5(19) 16.2(6) C24 5733(3) 2203(2) −207(2) 18.3(6)C34 4164(3) 1656(2) 1979(2) 16.6(6) C11 −695(3) 7200(2) 10304.5(19) 17.2(6) C12  267(3) 7915(2) 9953.6(19)  14.2(6) C23 4754(3) 2918(2) 127(2) 17.0(6) C27 4221(3) 3614(2) −494(2) 18.1(6) C8  800(3) 8626(2)10566(2)  17.0(6) C28 3315(3) 4357(2) −324(2) 18.6(6) C4 2436(4)10034(2)  8218(2) 23.3(7) C7 1688(3) 9377(2) 10382(2)  16.9(6) C292969(3) 4399(2)  492(2) 18.0(6) C9  237(3) 8445(2) 11388(2)  20.4(6) C382557(3) 2633(3) 4320(2) 24.9(7) C2 1458(3) 8717(2) 8931.9(19)  15.1(6)C6 2005(3) 9409(2) 9557(2) 17.2(6) C26 4804(3) 3424(2) −1310(2)  21.8(7)C31 2476(4) 5023(2) 1822(2) 24.4(7) C5 2927(3) 10137(2)  9193(2) 19.6(6)C16 2044(3) 7389(3) 5427(2) 22.4(7) C25 5416(4) 2367(3) −1181(2) 24.1(7) C15 1514(3) 7144(2) 6188(2) 21.6(6) C33 3503(3) 3713(2) 1124(2)16.9(6) C37 3005(3) 2117(3) 5067(2) 23.8(7) C30 2028(3) 5128(2)  844(2)20.5(6) C10 −360(4) 7379(2) 11275(2)  23.9(7) C36 3748(3) 1285(3)4821(2) 24.5(7) C17 2020(4) 6535(3) 4974(2) 28.3(7) C14 1181(3) 6178(2)6137.8(19)  19.0(6) C35 3710(3) 1326(2) 3973(2) 23.7(7) C19 2583(3)8401(3) 5214(2) 26.0(7) C3 1902(3) 8960(2) 8090(2) 19.0(6) C32 3002(3)3944(2) 1954(2) 21.0(6) C40 2768(4) 2390(3) 5955(2) 33.7(8) C20 1804(4)9231(3) 5566(3) 34.6(8) C39 1810(4) 3575(3) 4092(3) 35.7(8) C42 1313(4)2062(3) 6087(3) 40.3(9) C21 4139(4) 8447(3) 5541(3) 40.0(9) C18 2406(5)6256(3) 4130(3)  44.7(10) C41 3893(5) 1934(4) 6622(3)  54.3(12)

Single crystal X-ray crystallographic analysis was performed on compound181b. FIG. 2 shows ball and stick models of the asymmetrical unitcontaining two crystallographically independent molecules of compound181b, with hydrogen atoms omitted for clarity. Table N below showsfractional atomic coordinates of compound 181b.

TABLE N Fractional Atomic Coordinates (×10⁴) and Equivalent IsotropicDisplacement Parameters (Å² × 10³) for Example 3. U_(eq) is defined as ⅓of the trace of the orthogonalised U_(IJ) tensor. Atom x y z U(eq) S19264.0(7)  4621.3(5)  3094.0(4)  16.15(17) S2 5705.1(7)  9485.8(5) 6733.7(4)  19.00(17) O1 7853(2) 3305.2(16)  1778.9(13)  18.6(4) O77027(2) 7842.4(18)  6357.2(15)  26.4(5) O2 10182(2)  5364.5(17) 3520.0(14)  23.6(5) O5 7131(2) 8368.0(19)  8192.5(15)  25.5(5) O38512(3) 4220.7(18)  4605.0(14)  26.6(5) O6 4770(2) 10133.7(19) 6200.8(15)  28.4(5) O8 7211(3) 6563(2) 3921.7(19)  38.6(7) O4 7597(3)1484(2) 5713.0(18)  37.3(6) N2 9933(3) 4006.4(19)  2465.8(16)  17.8(5)N1 9943(2) 2773(2) 1482.7(16)  16.3(5) N4 5051(3) 7745(2) 8421.8(17) 20.2(5) N3 7870(3) 5173(2) 2653.4(17)  18.4(5) N5 5031(3) 8923(2)7390.2(17)  19.9(5) C14 9136(3) 3353(2) 1894.3(18)  15.8(6) C1 9391(3)2043(2)  864.7(19) 17.4(6) N6 7031(3) 10109(2)  7191.6(19)  23.0(6) C305618(3) 7045(2) 9058(2) 19.3(6) C6 9205(3) 1370(2) −570(2) 20.1(6) C537446(4) 7363(3) 5675(2) 26.1(7) C32 4273(3) 7792(2) 10199(2)  20.6(6) C29731(3) 2078(2)  44.2(19) 16.8(6) C43 5846(3) 8333(2) 8016(2) 20.2(6) C310685(3)  2795(2) −304(2) 20.3(6) C37 7028(3) 5597(2) 9506(2) 21.2(6) C78316(3)  620(2) −386(2) 20.2(6) C35 5773(3) 6383(2) 10493(2)  20.7(6)C10 7573(4)  −36(3) 1780(2) 27.4(7) C36 6681(3) 5639(2) 10322(2) 21.2(6) C22 8481(3) 2845(3) 3816(2) 23.0(6) C8 8002(3)  584(2)  440(2)20.3(6) C39 7525(4) 4977(3) 8177(2) 28.0(7) C31 5248(3) 7078(2) 9867(2)19.6(6) C52 6981(3) 7875(3) 4927(2) 24.2(7) C12 8541(3) 1280(2)1066.4(19)  18.0(6) C34 5191(4) 6574(3) 11302(2)  24.8(7) C51 6252(4)8707(3) 5170(2) 26.7(7) C33 4585(4) 7630(3) 11175(2)  27.6(7) C247990(4) 3461(3) 5032(2) 30.5(8) C23 7962(3) 2603(3) 4580(2) 24.0(7) C506302(4) 8662(3) 6020(2) 25.4(7) C9 7077(3) −142(2)  804(2) 23.6(7) C387972(3) 4873(2) 9155(2) 23.5(7) C5 9763(4) 1551(3) −1391(2)  24.9(7) C416502(3) 6286(2) 8872(2) 20.5(6) C21 8811(3) 3816(2) 3866.6(19)  20.4(6)C4 10356(4)  2619(3) −1277(2)  28.3(7) C11 8099(3) 1036(2) 1909(2)22.6(6) C40 7006(3) 6055(3) 8044(2) 24.5(6) C25 7419(4) 1599(3) 4793(2)26.8(7) C58 8189(4) 6425(3) 5905(3) 37.6(9) C54 7221(4) 7601(3) 4036(2)34.1(8) C27 8195(4)  774(3) 4438(3) 38.1(9) C29 7607(6) 3737(3) 5874(3) 46.7(10) C56 8674(4) 7924(3) 3907(3)  42.4(10) C28 5872(4) 1551(3)4471(3)  44.2(10) C57 6101(6) 8060(4) 3369(3)  58.9(14)

Example 4

Example 4 (101′):N′-(1,2,3,5,6,7-hexahydro-s-indacen-4-ylcarbamoyl)-2-(2-hydroxypropan-2-yl)thiazole-5-sulfonimidamide

Example 4 (above) was synthesized according to the general methods inSchemes 2 and 3, as illustrated in Route 1 and Route 2 below.

Examples 5 and 6

Examples 5 and 6 (Stereochemistry not Assigned) Examples 5 (101) and 6(102): (S)- and(R)—N′-(1,2,3,5,6,7-hexahydro-s-indacen-4-ylcarbamoyl)-2-(2-hydroxypropan-2-yl)thiazole-5-sulfonimidamide

Examples 5 and 6 (above) were synthesized according to general methodsshown in Schemes 2 and 3, as illustrated in Route 1 and Route 2 below.

Example 7

Example 7 (194): Tert-butylN-(1,2,3,5,6,7-hexahydro-s-indacen-4-ylcarbamoyl)-2-(2-hydroxypropan-2-yl)thiazole-5-sulfonimidoylcarbamate

Example 7 was synthesized according to general method shown in Scheme 3,as illustrated in Route 2 below.

Route 1

Step 1:N-(tert-butyldimethylsilyl)-N′-(1,2,3,5,6,7-hexahydro-s-indacen-4-ylcarbamoyl)-2-(2-hydroxypropan-2-yl)thiazole-5-sulfonimidamide

Into a 50-mL round-bottom flask was placed a solution ofN′-(tert-butyldimethylsilyl)-2-(2-hydroxypropan-2-yl)thiazole-5-sulfonimidamide(336 mg, 1.0 mmol) in THF (10 mL). To this solution was added NaH (60%wt, 80 mg, 2.0 mmol) in portions at 0° C. The solution was stirred at 0°C. for 15 minutes, and this was followed by the addition of a solutionof 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (209 mg, 1.1 mmol) inTHF (5 mL) dropwise with stirring at RT. The resulting solution wasstirred for 12 h at RT. The reaction was then quenched by the additionof 10 mL of NH₄Cl (sat.). The resulting solution was extracted with 3×10mL of DCM and the combined organic layers were concentrated undervacuum. This resulted in 535 mg (crude) of the title compound as a brownoil. MS-ESI: 535.0 (M+1).

Step 2:N′-(1,2,3,5,6,7-hexahydro-s-indacen-4-ylcarbamoyl)-2-(2-hydroxypropan-2-yl)thiazole-5-sulfonimidamide

Into a 50-mL round-bottom flask was placed a solution ofN-(tert-butyldimethylsilyl)-N′-(1,2,3,5,6,7-hexahydro-s-indacen-4-ylcarbamoyl)-2-(2-hydroxypropan-2-yl)thiazole-5-sulfonimidamide(535 mg, crude, 1.0 mmol) in THF (10 mL). To this solution was addedHF/Py (70% wt, 143 mg, 5.0 mmol) dropwise at 0° C. The solution wasstirred at RT for 4 h. The reaction was then quenched by the addition of10 mL of water. The resulting solution was extracted with 3×10 mL ofethyl acetate and the combined organic layers were concentrated undervacuum. The crude product was purified by Prep-HPLC using Method E withACN/water (20% to 60% in 10 minutes). This resulted in 189 mg (45%, 2steps) of Example 4 as a white solid.

Example 4

MS-ESI: 421.0 (M+1). ¹H NMR (400 MHz, DMSO-d₆) δ 8.46 (br s, 1H), 8.04(s, 1H), 7.80 (br s, 2H), 6.86 (s, 1H) 6.28 (s, 1H), 2.88-2.71 (m, 4H),2.71-2.56 (m, 4H), 2.02-1.80 (m, 4H), 1.49 (s, 6H).

Step 2: Chiral Separation

The product obtained as described in the previous step (189 mg) wasresolved by Chiral-Prep-HPLC using the following conditions: Column,CHIRAL Cellulose-SB, 2*25 cm, 5 um; mobile phase, Hex (0.1% DEA) andEtOH (hold 20% EtOH over 16 min); Flow rate, 20 mL/min; Detector, UV254/220 nm. This resulted in 70 mg of Example 5 (front peak, 99% ee 101)as a white solid and 65 mg of Example 6 (second peak, 97.5% ee 102) as awhite solid. Absolute stereochemistry of these two isomers has not beenassigned.

Example 5

MS-ESI: 421.0 (M+1). ¹H NMR (400 MHz, DMSO-d₆) δ 8.43 (br s, 1H), 8.05(s, 1H), 7.83 (br s, 2H), 6.87 (s, 1H) 6.29 (s, 1H), 2.82-2.71 (m, 4H),2.71-2.56 (m, 4H), 2.02-1.80 (m, 4H), 1.50 (s, 6H).

Example 6

MS-ESI: 421.0 (M+1). ¹H NMR (400 MHz, DMSO-d₆) δ 8.41 (br s, 1H), 8.05(s, 1H), 7.83 (s, 2H), 6.87 (s, 1H) 6.27 (s, 1H), 2.82-2.71 (m, 4H),2.71-2.56 (m, 4H), 2.02-1.80 (m, 4H), 1.50 (s, 6H).

Route 2:

Step 1: Tert-butylN-(1,2,3,5,6,7-hexahydro-s-indacen-4-ylcarbamoyl)-2-(2-hydroxypropan-2-yl)thiazole-5-sulfonimidoylcarbamate

Tert-butyl(amino(2-(2-hydroxypropan-2-yl)thiazol-5-yl)(oxo)-λ⁶-sulfaneylidene)carbamate(12 g, 37 mmol) was dissolved in dried THF (200 mL). To the solution wasadded NaH (17.7 g, 60%, 44 mmol) in portions at 0° C. under nitrogenatmosphere, and then the mixture was stirred at 0° C. for 0.5 h. Freshlyprepared 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (7.4 g, 37 mmol)was dissolved in dried THF (50 mL) and the solution was added to thefront mixture dropwise at 0° C. The mixture was stirred at RT for 1 h.The reaction was quenched with ice-water (100 mL), and the pH value ofthe resulting solution was adjusted to 6 with HCO₂H. The solution wasextracted with EtOAc (3×200 mL) and the combined organic layers weredried over anhydrous Na₂SO₄ and concentrated to give 17.5 g of Example 7as a crude grey solid.

Example 7

MS-ESI: 521.0 (M+1). ¹H NMR (300 MHz, MeOD-d₄) δ 8.14 (s, 1H), 6.89 (s,1H), 3.00-2.60 (m, 8H), 2.20-1.90 (m, 4H), 1.51 (s, 6H), 1.37 (s, 9H).

Step 2:N′-(1,2,3,5,6,7-hexahydro-s-indacen-4-ylcarbamoyl)-2-(2-hydroxypropan-2-yl)thiazole-5-sulfonimidamide

The crude tert-butyl(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(2-hydroxypropan-2-yl)-thiazole-5-sulfonimidoyl)carbamate(crude 17.5 g) was dissolved in THF (200 mL). To the solution was addedHCl (200 mL, 4M in 1,4-dioxane) at RT. The mixture was stirred at RTovernight and concentrated. The residue was purified with SiO₂-gelcolumn and eluted with MeOH/DCM (5%) and further purified by reversecolumn with MeOH/water (50% to 80% in 50 minutes) to give 12 g ofExample 4 (51%, 2 steps) as a white solid.

Example 4

MS-ESI: 421.0 (M+1). ¹H NMR (400 MHz, DMSO-d₆) δ 8.46 (br s, 1H), 8.04(s, 1H), 7.80 (br s, 2H), 6.86 (s, 1H) 6.28 (s, 1H), 2.88-2.71 (m, 4H),2.71-2.56 (m, 4H), 2.02-1.80 (m, 4H), 1.49 (s, 6H).

Step 3: Chiral Separation

The product obtained as described in the previous step (12 g) wasresolved by Chiral-Prep-SFC using the following conditions: Column,CHIRALPAK IF, 2*25 cm, 5 um; Mobile Phase A: CO₂: 60, Mobile Phase B:MeOH (2 mM NH₃-MeOH): 40; Flow rate: 40 mL/min; Detector, UV 220 nm.This resulted in 3.8 g of Example 6 (front peak, 99% ee 102) as a whitesolid and 4.6 g of Example 5 (second peak, 97.5% ee 101) as a whitesolid. Absolute stereochemistry of these two isomers has not beenassigned.

Example 5

MS-ESI: 421.0 (M+1). ¹H NMR (400 MHz, DMSO-d₆) δ 8.43 (br s, 1H), 8.05(s, 1H), 7.83 (br s, 2H), 6.87 (s, 1H) 6.29 (s, 1H), 2.82-2.71 (m, 4H),2.71-2.56 (m, 4H), 2.02-1.80 (m, 4H), 1.50 (s, 6H).

Example 6

MS-ESI: 421.0 (M+1). ¹H NMR (400 MHz, DMSO-d₆) δ 8.41 (br s, 1H), 8.05(s, 1H), 7.83 (s, 2H), 6.87 (s, 1H) 6.27 (s, 1H), 2.82-2.71 (m, 4H),2.71-2.56 (m, 4H), 2.02-1.80 (m, 4H), 1.50 (s, 6H).

Example 8

Example 8 (270):N′-(8-fluoro-1,2,3,5,6,7-hexahydro-s-indacen-4-ylcarbamoyl)-4-(2-hydroxypropan-2-yl)-N-methylthiophene-2-sulfonimidamide(Scheme 4)

Example 8 was synthesized according to the general method shown inScheme 4.

Into a 50-mL round-bottom flask purged with and maintained undernitrogen was placed a solution of4-fluoro-8-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (110 mg, 0.51mmol) in DCM (5 mL). To the solution were added TEA (153 mg, 1.51 mmol)and 4-(2-hydroxypropan-2-yl)-N′-methylthiophene-2-sulfonimidamide (120mg, 0.51 mmol). The resulting solution was stirred for 14 h at RT andthen was concentrated under vacuum. The crude product was purified byPrep-HPLC using method E eluted with a gradient of 30˜74% ACN. Thisresulted in 80 mg (35%) of Example 8 as a white solid.

Example 8

MS-ESI: 450.1 (M−1). ¹H NMR (400 MHz, DMSO-d₆) δ 8.50 (br s, 1H), 7.64(s, 1H), 7.59-7.50 (m, 2H), 5.23 (s, 1H), 2.84-2.69 (m, 8H), 2.50 (s,3H), 1.99 (t, J=7.2 Hz, 4H), 1.42 (d, J=2.8 Hz, 6H)

Example 9 (204)

N′-((2,6-dimethylpyridin-4-yl)carbamoyl)-4-methyl-5-(2-hydroxypropan-2-yl)thiophene-2-sulfonimidamide(Scheme 5)

Step 1: 4-Azido-2,6-dimethylpyridine

To the solution of 2,6-dimethylpyridine-4-carboxylic acid (151 mg, 1.0mmol) in dried toluene (15 mL). To the solution was added DPPA (825 mg,3.0 mmol) and TEA (303 mg, 3.0 mmol). The mixture was stirred at 60° C.for 4 h. The solution was concentrated under vacuum. This gave 900 mg(crude) of the title compound as yellow oil.

Step 2 & 3:N-(tert-butyldimethylsilyl)-N′-((2,6-dimethylpyridin-4-yl)carbamoyl)-5-(2-hydroxypropan-2-yl)-3-methylthiophene-2-sulfonimidamide

The 4-azido-2,6-dimethylpyridine (900 mg, crude) was dissolved in THF(20 mL). To the solution was added N′-(tert-butyldimethylsilyl)-5-(2-hydroxy propan-2-yl)-3-methylthiophene-2-sulfonimidamide(349 mg, 1.0 mmol) and NaOH (120 mg, 3.0 mmol). The mixture was stirredat 50° C. for 12 h. The solution was diluted with water 20 mL, then theresulting solution was extracted with 3×20 mL of ethyl acetate. Theorganic layers were combined, dried over anhydrous Na₂SO₄, thenconcentrated under vacuum. This gave 500 mg (crude) of the titlecompound as a yellow solid. MS-ESI: 497.0 (M+1).

Step 4:N′-((2,6-dimethylpyridin-4-yl)carbamoyl)-4-methyl-5-(2-hydroxypropan-2-yl)thiophene-2-sulfonimidamide

Into a 50-mL round-bottom flask was placed a solution ofN-(tert-butyldimethylsilyl)-N′-((2,6-dimethylpyridin-4-yl)carbamoyl)-4-methyl-5-(2-hydroxypropan-2-yl)thiophene-2-sulfonimidamide(500 mg, crude) in THF (10 mL), to this solution was added HF/Py (70%wt, 143 mg, 5.0 mmol) dropwise at 0° C. The solution was stirred at RTfor 4 h. The reaction was then quenched by the addition of 10 mL ofwater. The resulting solution was extracted with 3×10 mL of ethylacetate and the combined organic layers were concentrated under vacuum.The crude product was purified by Prep-HPLC using method E eluted with agradient of ACN/water (10% to 30% in 10 minutes). This resulted in 15 mg(4%, 4 steps) of Example 9 as a white solid. MS-ESI: 383.0 (M+1). ¹H NMR(300 MHz, DMSO-d₆) δ 9.31 (s, 1H), 7.53 (br s, 2H), 7.31 (s, 1H), 7.14(s, 2H), 5.81 (s, 1H), 2.28 (s, 6H), 2.23 (s, 3H), 1.50 (s, 6H).

TABLE 16 Examples in the following table were prepared using similarconditions as described in Example 1 and Scheme 1 from appropriatestarting materials. Example Final Target Exact Mass # Number StructureIUPAC Name [M + H]⁺ 10 180

N′-(4-fluoro-2,6- diisopropylphenylcarbamoyl)-4-(2-hydroxypropan-2-yl)-5-methylfuran- 2-sulfonimidamide 440.2 11 190

N′-(4-fluoro-2,6- diisopropylphenylcarbamoyl)-4-(2- hydroxypropan-2-yl)benzenesulfonimidamide 436.2 12 182

N′-(1,2,3,5,6,7-hexahydro-s-indacen- 4-ylcarbamoyl)-4-(2-hydroxypropan-2-yl)-5-methylthiophene-2- sulfonimidamide 434.1 13 191

2-fluoro-N′-(1,2,3,5,6,7-hexahydro- s-indacen-4-ylcarbamoyl)-4-(2-hydroxypropan-2- yl)benzenesulfonimidamide 432.2 14 177

N′-(8-chloro-1,2,3,5,6,7-hexahydro- s-indacen-4-ylcarbamoyl)-4-(2-hydroxypropan-2-yl)thiophene-2- sulfonimidamide 452.0 (M − 1) 15 185

N′-(4-cyano-3-fluoro-2,6- diisopropylphenylcarbamoyl)-2-(2-hydroxypropan-2-yl)thiazole-5- sulfonimidamide 468.2 16 186

N′-(1,2,3,5,6,7-hexahydro-5-indacen- 4-ylcarbamoyl)-1-isopropyl-1H-pyrazole-3-sulfonimidamide 388.1 17 187

N′-(4-(difluoromethoxy)-2,6- diisopropylphenylcarbamoyl)-3-fluoro-5-(2-hydroxypropan-2- yl)thiophene-2-sulfonimidamide 508.2 18 188

N′-(4-(difluoromethoxy)-2-ethyl-6- isopropylphenylcarbamoyl)-2-(2-hydroxypropan-2-yl)thiazole-5- sulfonimidamide 477.1 19 192

N′-(1,2,3,5,6,7-hexahydro-s-indacen- 4-ylcarbamoyl)-4-(2-hydroxypropan-2-yl)-2- methylbenzenesulfonimidamide 426.2 (M − 1) 20 189

N′-(2-cyclopropyl-4- (difluoromethoxy)-6-isopropylphenylcarbamoyl)-2-(2- hydroxypropan-2-yl)thiazole-5-sulfonimidamide 487.1 (M − 1) 21 178

N′-(4-fluoro-2,6- diisopropylphenylcarbamoyl)-2-(2-hydroxypropan-2-yl)thiazole-5- sulfonimidamide 441.1 (M − 1) 22 193

N′-(4-fluoro-2,6- diisopropylphenylcarbamoyl)-3-(2- hydroxypropan-2-yl)benzenesulfonimidamide 436.1 23 170

N′-(4-cyano-6-cyclopropyl-3-fluoro- 2-isopropylphenylcarbamoyl)-2-(2-hydroxypropan-2-yl)thiazole-5- sulfonimidamide 466.1 24 168

N′-(4-(difluoromethoxy)-2,6- diisopropylphenylcarbamoyl)-5-(2-hydroxypropan-2-yl)-3- methylthiophene-2-sulfonimidamide 504.3 25 171

N′-(4-(difluoromethoxy)-2,6- diisopropylphenylcarbamoyl)-2-(2-hydroxypropan-2-yl)thiazole-5- sulfonimidamide 491.1 26 122

N′-(8-cyano-1,2,3,5,6,7-hexahydro-s- indacen-4-ylcarbamoyl)-4-(2-hydroxypropan-2-yl)thiophene-2- sulfonimidamide 443.1 (M − 1) 27 120

N′-(8-(difluoromethoxy)-1,2,3,5,6,7- hexahydro-s-indacen-4-ylcarbamoyl)-2-(2-hydroxypropan-2- yl)thiazole-5-sulfonimidamide 487.128 125

4-((dimethylamino)methyl)-N′- (1,2,3,5,6,7-hexahydro-s-indacen-4-ylcarbamoyl)benzenesulfonimidamide 413.3 29 129

N′-(2-cyclopropyl-4- (difluoromethoxy)-6-isopropylphenylcarbamoyl)-4-(2- hydroxypropan-2-yl)-2-methylbenzenesulfonimidamide 496.2 30 213

3-fluoro-N′-(8-fluoro-1,2,3,5,6,7- hexahydro-s-indacen-4-ylcarbamoyl)-5-(2-hydroxypropan-2- yl)thiophene-2-sulfonimidamide 456.131 207

4-(2-hydroxypropan-2-yl)-5-methyl- N′-((3-methyl-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)furan-2- sulfonimidamide 432.2 32 195

4-(2-hydroxypropan-2-yl)-5-methyl- N′-((1-methyl-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)furan-2- sulfonimidamide 432.2

TABLE 17 Examples in the following table were prepared using similarconditions as described in Example 4 - route 1 and Scheme 2 fromappropriate starting materials. Example Final Target Exact Mass # NumberStructure IUPAC Name [M + H]⁺ 33 179

N′-(4-cyano-3-fluoro-2,6- diisopropylphenylcarbamoyl)-4-(2-hydroxypropan-2-yl)-5- methylfuran-2-sulfonimidamide 465.2 34 105

N′-(8-fluoro-1,2,3,5,6,7- hexahydro-s-indacen-4- ylcarbamoyl)-3-(2-hydroxypropan-2- yl)benzenesulfonimidamide 432.2 35 121

N′-(4-cyano-2,6- diisopropylphenylcarbamoyl)-5-(2-hydroxypropan-2-yl)thiazole- 2-sulfonimidamide 448.1 (M − 1) 36 145

4-((dimethylamino)methyl)-N′- (4-fluoro-2,6- diisopropylphenylcarbamoyl)benzenesulfonimidamide 435.2 37 131

N′-(2-cyclopropyl-4- (difluoromethoxy)-6- isopropylphenylcarbamoyl)-4-((dimethylamino)methyl)benzene- sulfonimidamide 481.3 38 132

N′-(4-(difluoromethoxy)-2,6- diisopropylphenylcarbamoyl)-5-(2-hydroxypropan-2-yl)thiazole- 2-sulfonimidamide 489.1 (M − 1) 39 144

N′-(4-fluoro-2,6- diisopropylphenylcarbamoyl)-5-(2-hydroxypropan-2-yl)thiazole- 2-sulfonimidamide 441.1 (M − 1) 40 149

N′-(4-fluoro-2,6- diisopropylphenylcarbamoyl)-4- (2-hydroxypropan-2-yl)thiophene-2-sulfonimidamide 440.1 (M − 1) 41 152

N′-(8-chloro-1,2,3,5,6,7- hexahydro-s-indacen-4-ylcarbamoyl)-2-fluoro-4-(2- hydroxypropan-2- yl)benzenesulfonimidamide466.2 42 150

N′-(4-fluoro-2,6- diisopropylphenylcarbamoyl)-4-(methylsulfonyl)benzene- sulfonimidamide 454.1 (M − 1) 43 167

N′-(8-cyano-1,2,3,5,6,7- hexahydro-s-indacen-4- ylcarbamoyl)-2-(2-hydroxypropan-2-yl)thiazole-5- sulfonimidamide 444.2 (M − 1) 44 106

N′-(8-fluoro-1,2,3,5,6,7- hexahydro-s-indacen-4- ylcarbamoyl)-2-(2-hydroxypropan-2-yl)thiazole-5- sulfonimidamide 437.1 (M − 1) 45 107

N′-(8-fluoro-1,2,3,5,6,7- hexahydro-s-indacen-4- ylcarbamoyl)-4-(2-hydroxypropan-2-yl)-5- methylfuran-2-sulfonimidamide 436.2 46 110

N′-(1,2,3,5,6,7-hexahydro-s- indacen-4-ylcarbamoyl)-3-(2-hydroxypropan-2- yl)benzenesulfonimidamide 414.2 47 151

2-fluoro-N′-(8-fluoro-1,2,3,5,6,7- hexahydro-s-indacen-4-ylcarbamoyl)-4-(2- hydroxypropan-2- yl)benzenesulfonimidamide 448.1 (M− 1) 48 154

4-((dimethylamino)methyl)-2- fluoro-N′-(1,2,3,5,6,7-hexahydro-s-indacen-4- ylcarbamoyl)benzene- sulfonimidamide 431.2 49 148

N′-(4-fluoro-2,6- diisopropylphenylcarbamoyl)-5- (2-hydroxypropan-2-yl)thiophene-2-sulfonimidamide 442.2 50 153

2-chloro-N′-(8-fluoro-1,2,3,5,6,7- hexahydro-s-indacen-4-ylcarbamoyl)-4-(2- hydroxypropan-2- yl)benzenesulfonimidamide 464.1 (M− 1) 51 109

3-((dimethylamino)methyl)-N′- (1,2,3,5,6,7-hexahydro-s- indacen-4-ylcarbamoyl)benzene- sulfonimidamide 411.1 (M − 1) 52 135

N′-((1,2,3,5,6,7-hexahydro-s- indacen-4-yl)carbamoyl)-4-(2-hydroxypropan-2-yl)-3- methylbenzenesulfonimidamide 428.2 53 134

N′-((1,2,3,5,6,7-hexahydro-s- indacen-4-yl)carbamoyl)-2-(2-hydroxypropan-2-yl)-4- methylthiazole-5- sulfonimidamide 435.1 54 130

N′-((2-cyclopropyl-4- (difluoromethoxy)-6- isopropylphenyl)carbamoyl)-2-fluoro-4-(2-hydroxypropan-2- yl)benzenesulfonimidamide 500.2 55 212

2-fluoro-N′-((8-fluoro- 1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-5-(2- hydroxypropan-2- yl)benzenesulfonimidamide 450.256 205

3-fluoro-N′-((8-fluoro- 1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-5-(2- hydroxypropan-2- yl)benzenesulfonimidamide 450.257 143

N′-((4-(difluoromethoxy)-2,6- diisopropylphenyl)carbamoyl)-5-(2-hydroxypropan-2-yl)-4- methylthiophene-2- sulfonimidamide 504.2 58206

4-fluoro-N′-((8-fluoro- 1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-3-(2- hydroxypropan-2- yl)benzenesulfonimidamide 450.259 108

N′-((8-fluoro-1,2,3,5,6,7- hexahydro-s-indacen-4- yl)carbamoyl)-2-(2-hydroxypropan-2-yl)-4- methylthiazole-5- sulfonimidamide 453.1 60 202

3-fluoro-N′-((1,2,3,5,6,7- hexahydro-s-indacen-4- yl)carbamoyl)-4-(2-hydroxypropan-2- yl)benzenesulfonimidamide 432.2 61 208

N′-((8-fluoro-1,2,3,5,6,7- hexahydro-s-indacen-4- yl)carbamoyl)-4-(2-hydroxypropan-2-yl)thiazole-2- sulfonimidamide 439.1 62 197

N′-((3-fluoro-2,6- diisopropylphenyl)carbamoyl)-2-(2-hydroxypropan-2-yl)thiazole- 5-sulfonimidamide 443.2 63 196

N′-((4-fluoro-2,6- diisopropylphenyl)carbamoyl)-3-(methylsulfonyl)benzene- sulfonimidamide 456.1 64 124

N′-((1,2,3,5,6,7-hexahydro-s- indacen-4-yl)carbamoyl)-5-(2-hydroxypropan-2-yl)thiazole-2- sulfonimidamide 421.1 65 173

N′-((4-cyano-2,6- diisopropylphenyl)carbamoyl)-3-fluoro-5-(2-hydroxypropan-2- yl)thiophene-2-sulfonimidamide 467.2 66 172

N′-((4-cyano-2,6- diisopropylphenyl)carbamoyl)-3,5-bis(2-hydroxypropan-2- yl)benzenesulfonimidamide 501.2 67 174

3-cyano-N′-((4-cyano-2,6- diisopropylphenyl)carbamoyl)-5-(2-hydroxypropan-2- yl)benzenesulfonimidamide 468.2 68 158

N′-((4-cyano-2,6- diisopropylphenyl)carbamoyl)-3- (hydroxymethyl)-4-(2-hydroxypropan-2- yl)benzenesulfonimidamide 473.2 69 220

N′-((8-cyano-1,2,3,5,6,7- hexahydro-s-indacen-4- yl)carbamoyl)-4-(hydroxymethyl)-2-(2- hydroxypropan-2-yl)thiazole-5- sulfonimidamide476.1 70 157

N-((4-cyano-2,6- diisopropylphenyl)carbamoyl)-4- (hydroxymethyl)-2-(2-hydroxypropan-2-yl)thiazole-5- sulfonimidamide 480.2 71 161

N-((4-cyano-3-fluoro-2,6- diisopropylphenyl)carbamoyl)-4-(hydroxymethyl)-2-(2- hydroxypropan-2-yl)thiazole-5- sulfonimidamide498.2 72 159

N′-((4-cyano-3-fluoro-2,6- diisopropylphenyl)carbamoyl)-2-(1,2-dihydroxypropan-2- yl)thiazole-5-sulfonimidamide 484.1 73 165

N′-((4-cyano-2,6- diisopropylphenyl)carbamoyl)-4-(methylsulfonyl)benzene- sulfonimidamide 463.1 74 183

N′-(1,2,3,5,6,7-hexahydro-s- indacen-4-ylcarbamoyl)-4-(2-hydroxypropan-2-yl)thiophene-2- sulfonimidamide 418.1 (M − 1) 75 176

N′-(8-fluoro-1,2,3,5,6,7- hexahydro-s-indacen-4- ylcarbamoyl)-4-(2-hydroxypropan-2-yl)thiophene-2- sulfonimidamide 438.0 76 136

N′-(1,2,3,5,6,7-hexahydro-s- indacen-4-ylcarbamoyl)-4-(2-hydroxypropan-2-yl)furan-2- sulfonimidamide 404.2 77 209

N′-(1,2,3,5,6,7-hexahydro-s- indacen-4-ylcarbamoyl)-4-(2-hydroxypropan-2-yl)thiazole-2- sulfonimidamide 421.1

TABLE 18 Examples in the following table were prepared using similarconditions as described in Example 9 and Scheme 5 from appropriatematerials. Example Final Target Exact Mass # Number Structure IUPAC Name[M + H]⁺ 78 203

N-((2,6-dimethylpyridin- 4-yl)carbamoyl)-5-(2- hydroxypropan-2-yl)thiophene-2- sulfonimidamide 369.1

TABLE 19 Examples in the following table were obtained from chiral HPLCresolutions of racemic examples described above. The chiral column andeluents are listed in the table. As a convention, the faster-elutingenantiomer is always listed first in the table followed by theslower-eluting enantiomer of the pair. The symbol * at a chiral centerdenotes that this chiral center has been resolved and the absolutestereochemistry at that center has not been determined. Final LC-MS Ex.Target [M + # Number Structure IUPAC Name Column Eluents H]⁺  79 180a or180b

(S)-or (R)- N′-(4-fluoro-2,6- diisopropylphenylcarbamoyl)-4-(2-hydroxypropan-2-yl)-5-methylfuran- 2-sulfonimidamide ChiralPak ID, 2*25cm, 5 um 20% EtOH in Hex 440.3  80 180b or 180a

(R)-or (S)- N′-(4-fluoro-2,6- diisopropylphenylcarbamoyl)-4-(2-hydroxypropan-2-yl)-5-methylfuran- 2-sulfonimidamide ChiralPak ID, 2*25cm, 5 um 20% EtOH in Hex 440.3  81 179a or 179b

(S)-or (R)- N′-(4-cyano-3-fluoro-2,6- diisopropylphenylcarbamoyl)-4-(2-hydroxypropan-2-yl)-5-methylfuran- 2-sulfonimidamide ChiralPak ID, 2*25cm, 5 um 23% EtOH in Hex 465.3  82 179b or 179a

(R)-or (S)- N′-(4-cyano-3-fluoro-2,6- diisopropylphenylcarbamoyl)-4-(2-hydroxypropan-2-yl)-5- methylfuran-2-sulfonimidamide ChiralPak ID, 2*25cm, 5 um 23% EtOH in Hex 465.3  83 190a or 190b

(S)-or (R)- N′-(4-fluoro-2,6- diisopropylphenylcarbamoyl)-4-(2-hydroxypropan-2- yl)benzenesulfonimidamide ChiralPak ID, 2*25 cm, 5um 20% EtOH in Hex 436.2  84 190b or 190a

(R)-or (S)- N′-(4-fluoro-2,6- diisopropylphenylcarbamoyl)-4-(2-hydroxypropan-2- yl)benzenesulfonimidamide ChiralPak ID, 2*25 cm, 5um 20% EtOH in Hex 436.2  85 182a or 182b

(S)-or (R)- N′-(1,2,3,5,6,7-hexahydro-s- indacen-4-ylcarbamoyl)-4-(2-hydroxypropan-2-yl)-5- methylthiophene-2-sulfonimidamide ChiralPak IC,2*25 cm, 5 um 20% EtOH in Hex 434.1  86 182b or 182a

(R)-or (S)- N′-(1,2,3,5,6,7-hexahydro-s- indacen-4-ylcarbamoyl)-4-(2-hydroxypropan-2-yl)-5- methylthiophene-2-sulfonimidamide ChiralPak IC,2*25 cm, 5 um 20% EtOH in Hex 434.1  87 191a or 191b

(S)-or (R)- 2-fluoro-N′-(1,2,3,5,6,7-hexahydro-s-indacen-4-ylcarbamoyl)-4-(2- hydroxypropan-2-yl)benzenesulfonimidamide ChiralPak IG, 2*25 cm, 5 um 30% IPA in Hex(0.1% DEA) 430.1 (M − 1)  88 191b or 191a

(R)-or (S)- 2-fluoro-N′-(1,2,3,5,6,7-hexahydro-s-indacen-4-ylcarbamoyl)-4-(2- hydroxypropan-2-yl)benzenesulfonimidamide ChiralPak IG, 2*25 cm, 5 um 30% IPA in Hex(0.1% DEA) 430.1 (M − 1)  89 177a or 177b

(S)-or (R)- N′-(8-chloro-1,2,3,5,6,7-hexahydro-s-indacen-4-ylcarbamoyl)-4-(2- hydroxypropan-2-yl)thiophene-2-sulfonimidamide ChiralPak ID, 2*25 cm, 5 um 20% EtOH in Hex (0.1% DEA)452.0 (M − 1)  90 177b or 177a

(R)-or (S)- N′-(8-chloro-1,2,3,5,6,7-hexahydro-s-indacen-4-ylcarbamoyl)-4-(2- hydroxypropan-2-yl)thiophene-2-sulfonimidamide ChiralPak ID, 2*25 cm, 5 um 20% EtOH in Hex (0.1% DEA)452.0 (M − 1)  91 185a or 185b

(S)-or (R)- N′-(4-cyano-3-fluoro-2,6- diisopropylphenylcarbamoyl)-2-(2-hydroxypropan-2-yl)thiazole-5- sulfonimidamide ChiralPak ID, 2*25 cm, 5um 30% EtOH in Hex (0.1% DEA) 466.1 (M − 1)  92 185b or 185a

(R)-or (S)- N′-(4-cyano-3-fluoro-2,6- diisopropylphenylcarbamoyl)-2-(2-hydroxypropan-2-yl)thiazole-5- sulfonimidamide ChiralPak ID, 2*25 cm, 5um 30% EtOH in Hex (0.1% DEA) 466.1 (M − 1)  93 186a or 186b

(S)-or (R)- N′-(1,2,3,5,6,7-hexahydro-s- indacen-4-ylcarbamoyl)-1-isopropyl-1H-pyrazole-3- sulfonimidamide ChiralPak IG, 2*25 cm, 5 um 30%EtOH in Hex (0.1% DEA) 388.1  94 186b or 186a

(R)-or (S)- N′-(1,2,3,5,6,7-hexahydro-s- indacen-4-ylcarbamoyl)-1-isopropyl-1H-pyrazole-3- sulfonimidamide ChiralPak IG, 2*25 cm, 5 um 30%EtOH in Hex (0.1% DEA) 388.1  95 187a or 187b

(S)-or (R)- N′-(4-(difluoromethoxy)-2,6- diisopropylphenylcarbamoyl)-3-fluoro-5-(2-hydroxypropan-2- yl)thiophene-2-sulfonimidamide ChiralPakID, 2*25 cm, 5 um 20% EtOH in Hex (0.1% DEA) 508.2  96 187b or 187a

(R)-or (S)- N′-(4-(difluoromethoxy)-2,6- diisopropylphenylcarbamoyl)-3-fluoro-5-(2-hydroxypropan-2- yl)thiophene-2-sulfonimidamide ChiralPakID, 2*25 cm, 5 um 20% EtOH in Hex (0.1% DEA) 508.2  97 188a or 188b

(S)-or (R)- N′-(4-(difluoromethoxy)-2-ethyl-6-isopropylphenylcarbamoyl)-2-(2- hydroxypropan-2-yl)thiazole-5-sulfonimidamide ChiralPak ID, 2*25 cm, 5 um 30% IPA in Hex (0.1% DEA)477.2  98 188b or 188a

(R)-or (S)- N′-(4-(difluoromethoxy)-2-ethyl-6-isopropylphenylcarbamoyl)-2-(2- hydroxypropan-2-yl)thiazole-5-sulfonimidamide ChiralPak ID, 2*25 cm, 5 um 30% IPA in Hex (0.1% DEA)477.2  99 192a or 192b

(S)-or (R)- N′-(1,2,3,5,6,7-hexahydro-s- indacen-4-ylcarbamoyl)-4-(2-hydroxypropan-2-yl)-2- methylbenzenesulfonimidamide ChiralPak ID, 2*25cm, 5 um 30% EtOH in Hex (0.1% DEA) 428.2 100 192b or 192a

(R)-or (S)- N′-(1,2,3,5,6,7-hexahydro-s- indacen-4-ylcarbamoyl)-4-(2-hydroxypropan-2-yl)-2- methylbenzenesulfonimidamide ChiralPak ID, 2*25cm, 5 um 30% EtOH in Hex (0.1% DEA) 428.2 101 189a or 189b

(S)-or (R)- N′-(2-cyclopropyl-4- (difluoromethoxy)-6-isopropylphenylcarbamoyl)-2-(2- hydroxypropan-2-yl)thiazole-5-sulfonimidamide ChiralPak ID, 2*25 cm, 5 um 50% IPA in Hex (0.1% DEA)489.3 102 189b or 189a

(R)-or (S)- N′-(2-cyclopropyl-4- (difluoromethoxy)-6-isopropylphenylcarbamoyl)-2-(2- hydroxypropan-2-yl)thiazole-5-sulfonimidamide ChiralPak ID, 2*25 cm, 5 um 50% IPA in Hex (0.1% DEA)489.2 103 178a or 178b

(S)-or (R)- N′-(4-fluoro-2,6- diisopropylphenylcarbamoyl)-2-(2-hydroxypropan-2-yl)thiazole-5- sulfonimidamide ChiralPak ID, 2*25 cm, 5um 30% IPA (0.1% DEA) in Hex:DCM = 3:1 443.2 104 178b or 178a

(R)-or (S)- N′-(4-fluoro-2,6- diisopropylphenylcarbamoyl)-2-(2-hydroxypropan-2-yl)thiazole-5- sulfonimidamide ChiralPak ID, 2*25 cm, 5um 30% IPA (0.1% DEA) in Hex:DCM = 3:1 443.1 105 193a or 193b

(S)-or (R)- N′-(4-fluoro-2,6- diisopropylphenylcarbamoyl)-3-(2-hydroxypropan-2- yl)benzenesulfonimidamide ChiralPak IG, 2*25 cm, 5 um20% IPA in Hex (0.1% DEA) 436.2 106 193b or 193a

(R)-or (S)- N′-(4-fluoro-2,6- diisopropylphenylcarbamoyl)-3-(2-hydroxypropan-2- yl)benzenesulfonimidamide ChiralPak IG, 2*25 cm, 5 um20% IPA in Hex (0.1% DEA) 436.2 107 170a or 170b

(S)-or (R)- N′-(4-cyano-6-cyclopropyl-3-fluoro-2-isopropylphenylcarbamoyl)-2-(2- hydroxypropan-2-yl)thiazole-5-sulfonimidamide ChiralPak IG, 2*25 cm, 5 um 15% EtOH in Hex (0.1% DEA)466.1 108 170b or 170a

(R)-or (S)- N′-(4-cyano-6-cyclopropyl-3-fluoro-2-isopropylphenylcarbamoyl)-2-(2- hydroxypropan-2-yl)thiazole-5-sulfonimidamide ChiralPak IG, 2*25 cm, 5 um 15% EtOH in Hex (0.1% DEA)466.1 109 168a or 168b

(S)-or (R)- N′-(4-(difluoromethoxy)-2,6-diisopropylphenylcarbamoyl)-5-(2- hydroxypropan-2-yl)-3-methylthiophene-2-sulfonimidamide ChiralPak ID, 2*25 cm, 5 um 30% IPA inHex (0.1% DEA) 504.2 110 168b or 168a

(R)-or (S)- N′-(4-(difluoromethoxy)-2,6-diisopropylphenylcarbamoyl)-5-(2- hydroxypropan-2-yl)-3-methylthiophene-2-sulfonimidamide ChiralPak ID, 2*25 cm, 5 um 30% IPA inHex (0.1% DEA) 504.2 111 171a or 171b

(S)-or (R)- N′-(4-(difluoromethoxy)-2,6-diisopropylphenylcarbamoyl)-2-(2- hydroxypropan-2-yl)thiazole-5-sulfonimidamide ChiralPak ID, 2*25 cm, 5 um 50% IPA in Hex:DCM = 1:1489.1 (M − 1) 112 171b or 171a

(R)-or (S)- N′-(4-(difluoromethoxy)-2,6-diisopropylphenylcarbamoyl)-2-(2- hydroxypropan-2-yl)thiazole-5-sulfonimidamide ChiralPak ID, 2*25 cm, 5 um 50% IPA in Hex:DCM = 1:1489.1 (M − 1) 113 122a or 122b

(S)-or (R)- N′-(8-cyano-1,2,3,5,6,7-hexahydro-s-indacen-4-ylcarbamoyl)-4-(2- hydroxypropan-2-yl)thiophene-2-sulfonimidamide ChiralPak ID, 2*25 cm, 5 um 30% IPA in Hex 443.1 (M − 1)114 122b or 122a

(R)-or (S)- N′-(8-cyano-1,2,3,5,6,7-hexahydro-s-indacen-4-ylcarbamoyl)-4-(2- hydroxypropan-2-yl)thiophene-2-sulfonimidamide ChiralPak ID, 2*25 cm, 5 um 30% IPA in Hex 443.1 (M − 1)115 120a or 120b

(S)-or (R)- N′-(8-(difluoromethoxy)-1,2,3,5,6,7- hexahydro-s-indacen-4-ylcarbamoyl)-2-(2-hydroxypropan- 2-yl)thiazole-5-sulfonimidamide ChiralART Cellulose- SB 2*25 cm, 5 um 20% EtOH in Hex (0.1% DEA) 485.1 (M − 1)116 120b or 120a

(R)-or (S)- N′-(8-(difluoromethoxy)-1,2,3,5,6,7- hexahydro-s-indacen-4-ylcarbamoyl)-2-(2-hydroxypropan- 2-yl)thiazole-5-sulfonimidamide ChiralART Cellulose- SB 2*25 cm, 5 um 20% EtOH in Hex (0.1% DEA) 485.1 (M − 1)117 125a or 125b

(S)-or (R)- 4-((dimethylamino)methyl)-N′-(1,2,3,5,6,7-hexahydro-s-indacen- 4-ylcarbamoyl)benzene- sulfonimidamideChiralPak ID, 2*25 cm, 5 um 50% IPA in Hex:DCM = 3:1 413.2 118 125b or125a

(R)-or (S)- 4-((dimethylamino)methyl)-N′-(1,2,3,5,6,7-hexahydro-s-indacen-4- ylcarbamoyl)benzene- sulfonimidamideChiralPak ID, 2*25 cm, 5 um 50% IPA in Hex:DCM = 3:1 413.2 119 129a or129b

(S)-or (R)- N′-(2-cyclopropyl-4- (difluoromethoxy)-6-isopropylphenylcarbamoyl)-4-(2- hydroxypropan-2-yl)-2-methylbenzenesulfonimidamide ChiralPak ID, 2*25 cm, 5 um 50% IPA inHex:DCM = 3:1 496.2 120 129b or 129a

(R)-or (S)- N′-(2-cyclopropyl-4- (difluoromethoxy)-6-isopropylphenylcarbamoyl)-4-(2- hydroxypropan-2-yl)-2-methylbenzenesulfonimidamide ChiralPak ID, 2*25 cm, 5 um 50% IPA inHex:DCM = 3:1 496.2 121 112a or 112b

(S)-or (R)- 3-fluoro-N′-(8-fluoro-1,2,3,5,6,7- hexahydro-s-indacen-4-ylcarbamoyl)-5-(2-hydroxypropan- 2-yl)thiophene-2-sulfonimidamideChiralPak IG, 2*25 cm, 5 um 15% EtOH in Hex (0.1% DEA) 456.1 122 112b or112a

(R)-or (S)- 3-fluoro-N′-(8-fluoro-1,2,3,5,6,7- hexahydro-s-indacen-4-ylcarbamoyl)-5-(2-hydroxypropan-2- yl)thiophene-2-sulfonimidamideChiralPak IG, 2*25 cm, 5 um 15% EtOH in Hex (0.1% DEA) 456.1 128 105a or105b

(S)-or (R)- N′-(8-fluoro-1,2,3,5,6,7-hexahydro-s-indacen-4-ylcarbamoyl)-3-(2- hydroxypropan-2-yl)benzenesulfonimidamide ChiralPak ID, 2*25 cm, 5 um 40% EtOH in Hex432.1 129 105b or 105a

(R)-or (S)- N′-(8-fluoro-1,2,3,5,6,7-hexahydro-s-indacen-4-ylcarbamoyl)-3-(2- hydroxypropan-2-yl)benzenesulfonimidamide ChiralPak ID, 2*25 cm, 5 um 40% EtOH in Hex432.1 130 121a or 121b

(S)-or (R)- N′-(4-cyano-2,6- diisopropylphenylcarbamoyl)-5-(2-hydroxypropan-2-yl)thiazole-2- sulfonimidamide ChiralPak ID, 2*25 cm, 5um 40% EtOH in Hex 448.1 (M − 1) 131 121b or 121a

(R)-or (S)- N′-(4-cyano-2,6- diisopropylphenylcarbamoyl)-5-(2-hydroxypropan-2-yl)thiazole-2- sulfonimidamide ChiralPak ID, 2*25 cm, 5um 40% EtOH in Hex 448.1 (M − 1) 132 145a or 145b

(S)-or (R)- 4-((dimethylamino)methyl)-N′-(4- fluoro-2,6-diisopropyl-phenylcarbamoyl)benzene- sulfonimidamide ChiralPak IG, 2*25 cm, 5 um 30%EtOH in Hex 435.2 133 145b or 145a

(R)-or (S)- 4-((dimethylamino)methyl)-N′-(4- fluoro-2,6-diisopropyl-phenylcarbamoyl)benzene- sulfonimidamide ChiralPak IG, 2*25 cm, 5 um 30%EtOH in Hex 435.2 134 131a or 131b

(S)-or (R)- N′-(2-cyclopropyl-4- (difluoromethoxy)-6-isopropylphenylcarbamoyl)-4- ((dimethylamino)methyl)benzene-sulfonimidamide ChiralPak IG, 2*25 cm, 5 um 50% EtOH in Hex 481.2 135131b or 131a

(R)-or (S)- N′-(2-cyclopropyl-4- (difluoromethoxy)-6-isopropylphenylcarbamoyl)-4- ((dimethylamino)methyl)benzene-sulfonimidamide ChiralPak IG, 2*25 cm, 5 um 50% EtOH in Hex 481.2 136225a or 225b

(S)-or (R)- N′-(4-(difluoromethoxy)-2,6-diisopropylphenylcarbamoyl)-5-(2- hydroxypropan-2-yl)thiazole-2-sulfonimidamide ChiralPak IF, 2*25 cm, 5 um 20% MeOH (0.1% TFA) in CO₂489.1 (M − 1) 137 225b or 225a

(R)-or (S)- N′-(4-(difluoromethoxy)-2,6-diisopropylphenylcarbamoyl)-5-(2- hydroxypropan-2-yl)thiazole-2-sulfonimidamide ChiralPak IF, 2*25 cm, 5 um 20% MeOH (0.1% TFA) in CO₂489.1 (M − 1) 138 144a or 144b

(S)-or (R)- N′-(4-fluoro-2,6- diisopropylphenylcarbamoyl)-5-(2-hydroxypropan-2-yl)thiazole-2- sulfonimidamide ChiralPak IF, 2*25 cm, 5um 20% MeOH (0.1% TFA) in CO₂ 443.2 139 144b or 144a

(R)-or (S)- N′-(4-fluoro-2,6- diisopropylphenylcarbamoyl)-5-(2-hydroxypropan-2-yl)thiazole-2- sulfonimidamide ChiralPak IF, 2*25 cm, 5um 20% MeOH (0.1% TFA) in CO₂ 443.1 140 149a or 149b

(S)-or (R)- N′-(4-fluoro-2,6- diisopropylphenylcarbamoyl)-4-(2-hydroxypropan-2-yl)thiophene-2- sulfonimidamide ChiralPak ID, 2*25 cm, 5um 30% EtOH in Hex 440.1 (M − 1) 141 149b or 149a

(R)-or (S)- N′-(4-fluoro-2,6- diisopropylphenylcarbamoyl)-4-(2-hydroxypropan-2-yl)thiophene-2- sulfonimidamide ChiralPak ID, 2*25 cm, 5um 30% EtOH in Hex 440.1 (M − 1) 142 152a or 152b

(S)-or (R)- N′-(4-fluoro-2,6- diisopropylphenylcarbamoyl)-4-(2-hydroxypropan-2-yl)thiophene-2- sulfonimidamide ChiralPak IG, 2*25 cm, 5um 30% IPA in Hex 466.2 143 152b or 152a

(R)-or (S)- N′-(4-fluoro-2,6- diisopropylphenylcarbamoyl)-4-(2-hydroxypropan-2-yl)thiophene-2- sulfonimidamide ChiralPak IG, 2*25 cm, 5um 30% IPA in Hex 466.2 144 151a′ or 151b′

(S)-or (R)- N′-(4-fluoro-2,6- diisopropylphenylcarbamoyl)-4-(methylsulfonyl)benzene- sulfonimidamide Lux 5u Cellulose- 4, AXIAPacked, 2.12*25 cm, 5 um 35% MeOH (2 mM NH₃) in CO₂ 454.1 (M − 1) 145151b′ or 151a′

(R)-or (S)- N′-(4-fluoro-2,6- diisopropylphenylcarbamoyl)-4-(methylsulfonyl)benzene- sulfonimidamide Lux 5u Cellulose- 4, AXIAPacked, 2.12*25 cm, 5 um 35% MeOH (2 mM NH₃) in CO₂ 454.1 (M − 1) 146167a or 167b

(S)-or (R)- N′-(8-cyano-1,2,3,5,6,7-hexahydro-s-indacen-4-ylcarbamoyl)-2-(2- hydroxypropan-2-yl)thiazole-5-sulfonimidamide ChiralPak IC, 2*25 cm, 5 um 30% EtOH in Hex (0.1% DEA)444.1 (M − 1) 147 167b or 167a

(R)-or (S)- N′-(8-cyano-1,2,3,5,6,7-hexahydro-s-indacen-4-ylcarbamoyl)-2-(2- hydroxypropan-2-yl)thiazole-5-sulfonimidamide ChiralPak IC, 2*25 cm, 5 um 30% EtOH in Hex (0.1% DEA)444.1 (M − 1) 148 107a or 107b

(S)-or (R)- N′-(8-fluoro-1,2,3,5,6,7-hexahydro-s-indacen-4-ylcarbamoyl)-4-(2- hydroxypropan-2-yl)-5-methylfuran-2-sulfonimidamide ChiralPak ID, 2*25 cm, 5 um 50% IPA in Hex 434.1 (M− 1) 149 107b or 107a

(R)-or (S)- N′-(8-fluoro-1,2,3,5,6,7-hexahydro-s-indacen-4-ylcarbamoyl)-4-(2- hydroxypropan-2-yl)-5-methylfuran-2-sulfonimidamide ChiralPak ID, 2*25 cm, 5 um 50% IPA in Hex 434.1 (M− 1) 150 110a or 110b

(S)-or (R)- N′-(1,2,3,5,6,7-hexahydro-s-indacen-4-ylcarbamoyl)-3-(2-hydroxypropan- 2-yl)benzenesulfonimidamide ChiralPakIF, 2*25 cm, 5 um 30% EtOH in Hex 412.1 (M − 1) 151 110b or 110a

(R)-or (S)- N′-(1,2,3,5,6,7-hexahydro-s-indacen-4-ylcarbamoyl)-3-(2-hydroxypropan- 2-yl)benzenesulfonimidamide ChiralPakIF, 2*25 cm, 5 um 30% EtOH in Hex 412.1 (M − 1) 152 151a or 151b

(S)-or (R)- 2-fluoro-N′-(8-fluoro-1,2,3,5,6,7- hexahydro-s-indacen-4-ylcarbamoyl)-4-(2-hydroxypropan- 2-yl)benzenesulfonimidamide ChiralPakIG, 2*25 cm, 5 um 30% IPA in Hex 448.1 (M − 1) 153 151b or 151a

(R)-or (S)- 2-fluoro-N′-(8-fluoro-1,2,3,5,6,7- hexahydro-s-indacen-4-ylcarbamoyl)-4-(2-hydroxypropan- 2-yl)benzenesulfonimidamide ChiralPakIG, 2*25 cm, 5 um 30% IPA in Hex 448.1 (M − 1) 154 154a or 154b

(S)-or (R)- 4-((dimethylamino)methyl)-2-fluoro-N′-(1,2,3,5,6,7-hexahydro-s- indacen-4-ylcarbamoyl)benzene-sulfonimidamide ChiralPak IG, 2*25 cm, 5 um 30% EtOH in Hex 431.2 155154b or 154a

(R)-or (S)- 4-((dimethylamino)methyl)-2-fluoro-N′-(1,2,3,5,6,7-hexahydro-s-indacen- 4-ylcarbamoyl)benzene-sulfonimidamide ChiralPak IG, 2*25 cm, 5 um 30% EtOH in Hex 431.2 156148a or 148b

(S)-or (R)- N′-(4-fluoro-2,6- diisopropylphenylcarbamoyl)-5-(2-hydroxypropan-2-yl)thiophene-2- sulfonimidamide ChiralPak ID, 2*25 cm, 5um 30% EtOH in Hex 442.1 157 148b or 148a

(R)-or (S)- N′-(4-fluoro-2,6- diisopropylphenylcarbamoyl)-5-(2-hydroxypropan-2-yl)thiophene-2- sulfonimidamide ChiralPak ID, 2*25 cm, 5um 30% EtOH in Hex 442.1 158 153a or 153b

(S)-or (R)- 2-chloro-N′-(8-fluoro-1,2,3,5,6,7- hexahydro-s-indacen-4-ylcarbamoyl)-4-(2-hydroxypropan- 2-yl)benzenesulfonimidamide ChiralPakIF, 2*25 cm, 5 um 30% EtOH in Hex 464.1 (M − 1) 159 153a or 153b

(R)-or (S)- 2-chloro-N′-(8-fluoro-1,2,3,5,6,7- hexahydro-s-indacen-4-ylcarbamoyl)-4-(2-hydroxypropan- 2-yl)benzenesulfonimidamide ChiralPakIF, 2*25 cm, 5 um 30% EtOH in Hex 464.1 (M − 1) 160 109a or 109b

(S)-or (R)- 3-((dimethylamino)methyl)-N′-(1,2,3,5,6,7-hexahydro-s-indacen- 4-ylcarbamoyl)benzene- sulfonimidamideChiralPak ID, 2*25 cm, 5 um 50% EtOH in Hex (0.1% DEA) 413.1 161 109b or109a

(R)-or (S)- 3-((dimethylamino)methyl)-N′-(1,2,3,5,6,7-hexahydro-s-indacen- 4-ylcarbamoyl)benzene- sulfonimidamideChiralPak ID, 2*25 cm, 5 um 50% EtOH in Hex (0.1% DEA) 413.1 162 135a or135b

(S)-or (R)- N′-((1,2,3,5,6,7-hexahydro-s- indacen-4-yl)carbamoyl)-4-(2-hydroxypropan-2-yl)-3- methylbenzenesulfonimidamide ChiralPak ID, 2*25cm, 5 um 30% IPA in Hex 428.2 163 135b or 135a

(R)-or (S)- N′-((1,2,3,5,6,7-hexahydro-s- indacen-4-yl)carbamoyl)-4-(2-hydroxypropan-2-yl)-3- methylbenzenesulfonimidamide ChiralPak ID, 2*25cm, 5 um 30% IPA in Hex 428.2 164 134a or 134b

(S)-or (R)- N′-((1,2,3,5,6,7-hexahydro-s- indacen-4-yl)carbamoyl)-2-(2-hydroxypropan-2-yl)-4- methylthiazole-5-sulfonimidamide ChiralPak ID,2*25 cm, 5 um 30% IPA in Hex 435.1 165 134b or 134a

(R)-or (S)- N′-((1,2,3,5,6,7-hexahydro-s- indacen-4-yl)carbamoyl)-2-(2-hydroxypropan-2-yl)-4- methylthiazole-5-sulfonimidamide ChiralPak ID,2*25 cm, 5 um 30% IPA in Hex 435.1 166 130a or 130b

(S)-or (R)- N′-((2-cyclopropyl-4- (difluoromethoxy)-6-isopropylphenyl)carbamoyl)-2- fluoro-4-(2-hydroxypropan-2-yl)benzenesulfonimidamide ChiralPak ID, 2*25 cm, 5 um 40% IPA in Hex500.2 167 130b or 130a

(R)-or (S)- N′-((2-cyclopropyl-4- (difluoromethoxy)-6-isopropylphenyl)carbamoyl)-2- fluoro-4-(2-hydroxypropan-2-yl)benzenesulfonimidamide ChiralPak ID, 2*25 cm, 5 um 40% IPA in Hex500.2 168 212a or 212b

(S)-or (R)- 2-fluoro-N′-((8-fluoro-1,2,3,5,6,7- hexahydro-s-indacen-4-yl)carbamoyl)-5-(2- hydroxypropan-2- yl)benzenesulfonimidamide ChiralPakID, 2*25 cm, 5 um 40% EtOH in Hex 450.2 169 212b or 212a

(S)-or (R)- 2-fluoro-N′-((8-fluoro-1,2,3,5,6,7- hexahydro-s-indacen-4-yl)carbamoyl)-5-(2- hydroxypropan-2- yl)benzenesulfonimidamide ChiralPakID, 2*25 cm, 5 um 40% EtOH in Hex 450.2 170 205a or 205b

(R)-or (S)- 3-fluoro-N′-((8-fluoro-1,2,3,5,6,7- hexahydro-s-indacen-4-yl)carbamoyl)-5-(2- hydroxypropan-2- yl)benzenesulfonimidamide ChiralART Cellulose- SB, 2*25 cm, 5 um 30% EtOH in Hex 450.2 171 205a or 205b

(S)-or (R)- 3-fluoro-N′-((8-fluoro-1,2,3,5,6,7- hexahydro-s-indacen-4-yl)carbamoyl)-5-(2- hydroxypropan-2- yl)benzenesulfonimidamide ChiralART Cellulose- SB, 2*25 cm, 5 um 40% EtOH in Hex 450.2 172 143a or 143b

(S)-or (R)- N′-((4-(difluoromethoxy)-2,6- diisopropylphenyl)carbamoyl)-5-(2-hydroxypropan-2-yl)-4- methylthiophene-2- sulfonimidamide ChiralPakID, 2*25 cm, 5 um 30% EtOH in Hex 504.2 173 143b or 143a

(R)-or (S)- N′-((4-(difluoromethoxy)-2,6-diisopropylphenyl)carbamoyl)-5- (2-hydroxypropan-2-yl)-4-methylthiophene-2- sulfonimidamide ChiralPak ID, 2*25 cm, 5 um 30% EtOHin Hex 504.2 174 206a or 206b

(S)-or (R)- 4-fluoro-N′-((8-fluoro-1,2,3,5,6,7- hexahydro-s-indacen-4-yl)carbamoyl)-3-(2-hydroxypropan- 2-yl)benzenesulfonimidamide ChiralPakID, 2*25 cm, 5 um 30% EtOH in Hex (8 mM NH₃•MeOH) 450.2 175 206b or 206a

(R)-or (S)- 4-fluoro-N′-((8-fluoro-1,2,3,5,6,7- hexahydro-s-indacen-4-yl)carbamoyl)-3-(2-hydroxypropan- 2-yl)benzenesulfonimidamide ChiralPakID, 2*25 cm, 5 um 30% EtOH in Hex (8 mM NH₃•MeOH) 450.2 176 108a or 108b

(S)-or (R)- N′-((8-fluoro-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(2- hydroxypropan-2-yl)-4-methylthiazole-5-sulfonimidamide ChiralPak IG, 2*25 cm, 5 um 30% IPA inHex 453.1 177 108b or 108a

(R)-or (S)- N′-((8-fluoro-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(2- hydroxypropan-2-yl)-4-methylthiazole-5-sulfonimidamide ChiralPak IG, 2*25 cm, 5 um 40% IPA inHex 453.1 178 202a or 202b

(S)-or (R)- 3-fluoro-N′-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-(2- hydroxypropan-2-yl)benzenesulfonimidamide Chiral ART Cellulose- SB, 2*25 cm, 5 um 50%EtOH in Hex (8 mM NH₃•MeOH) 432.2 179 202b or 202a

(R)-or (S)- 3-fluoro-N′-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-(2- hydroxypropan-2-yl)benzenesulfonimidamide Chiral ART Cellulose- SB, 2*25 cm, 5 um 50%EtOH in Hex (8 mM NH₃•MeOH) 432.2 180 116a or 116b

(S)-or (R)- N′-((8-fluoro-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-(2- hydroxypropan-2-yl)-N-methylthiophene-2-sulfonimidamide ChiralPak IG, 2*25 cm, 5 um 30% EtOHin Hex 452.1 181 116b or 116a

(R)-or (S)- N′-((8-fluoro-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-(2- hydroxypropan-2-yl)-N-methylthiophene-2-sulfonimidamide ChiralPak IG, 2*25 cm, 5 um 30% EtOHin Hex 452.1 182 173a or 173b

(S)-or (R)- N′-((4-cyano-2,6- diisopropylphenyl)carbamoyl)-3-fluoro-5-(2-hydroxypropan-2- yl)thiophene-2-sulfonimidamide ChiralPakID, 2*25 cm, 5 um 15% EtOH in Hex (0.1% DEA) 467.2 183 173b or 173a

(R)-or (S)- N′-((4-cyano-2,6- diisopropylphenyl)carbamoyl)-3-fluoro-5-(2-hydroxypropan-2- yl)thiophene-2-sulfonimidamide ChiralPakID, 2*25 cm, 5 um 15% EtOH in Hex (0.1% DEA) 467.2 184 174a or 174b

(S)-or (R)- 3-cyano-N′-((4-cyano-2,6- diisopropylphenyl)carbamoyl)-5-(2-hydroxypropan-2- yl)benzenesulfonimidamide ChiralPak IG, 2*25 cm, 5 um15% EtOH in Hex (0.1% DEA) 468.2 185 174b or 174a

(R)-or (S)- 3-cyano-N′-((4-cyano-2,6- diisopropylphenyl)carbamoyl)-5-(2-hydroxypropan-2- yl)benzenesulfonimidamide ChiralPak IG, 2*25 cm, 5 um15% EtOH in Hex (0.1% DEA) 468.2 186 223a or 223b

(S)-or (R)- N′-((4-cyano-2,6- diisopropylphenyl)carbamoyl)-5-(2-hydroxypropan-2-yl)thiophene-2- sulfonimidamide ChiralPak ID, 2*25 cm, 5um 30% EtOH in Hex (0.1% DEA) 449.2 187 223b or 223a

(R)-or (S)- N′-((4-cyano-2,6- diisopropylphenyl)carbamoyl)-5-(2-hydroxypropan-2-yl)thiophene-2- sulfonimidamide ChiralPak ID, 2*25 cm, 5um 30% EtOH in Hex (0.1% DEA) 449.2 188 158a or 158b

(S)-or (R)- N′-((4-cyano-2,6- diisopropylphenyl)carbamoyl)-3-(hydroxymethyl)-4-(2- hydroxypropan-2- yl)benzenesulfonimidamideChiralPak ID, 2*25 cm, 5 um 30% EtOH in Hex (0.1% DEA) 473.2 189 158b or158a

(R)-or (S)- N′-((4-cyano-2,6- diisopropylphenyl)carbamoyl)-3-(hydroxymethyl)-4-(2- hydroxypropan-2- yl)benzenesulfonimidamideChiralPak ID, 2*25 cm, 5 um 30% EtOH in Hex (0.1% DEA) 473.2 190 220a or220b

(S)-or (R)- N′-((8-cyano-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4- (hydroxymethyl)-2-(2-hydroxypropan-2-yl)thiazole-5- sulfonimidamide ChiralPak IF, 2*25 cm, 5um MeOH (0.1% DEA) 476.1 191 220b or 220a

(R)-or (S)- N′-((8-cyano-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4- (hydroxymethyl)-2-(2-hydroxypropan-2-yl)thiazole-5- sulfonimidamide ChiralPak IF, 2*25 cm, 5um MeOH (0.1% DEA) 476.1 192 157a or 157b

(S)-or (R)- N′-((4-cyano-2,6- diisopropylphenyl)carbamoyl)-4-(hydroxymethyl)-2-(2- hydroxypropan-2-yl)thiazole-5- sulfonimidamideChiralPak IC, 2*25 cm, 5 um 15% EtOH in Hex 480.2 193 157b or 157a

(R)-or (S)- N′-((4-cyano-2,6- diisopropylphenyl)carbamoyl)-4-(hydroxymethyl)-2-(2- hydroxypropan-2-yl)thiazole-5- sulfonimidamideChiralPak IC, 2*25 cm, 5 um 15% EtOH in Hex 480.2 194 161a or 161b

(S)-or (R)- N′-((4-cyano-3-fluoro-2,6- diisopropylphenyl)carbamoyl)-4-(hydroxymethyl)-2-(2- hydroxypropan-2-yl)thiazole-5- sulfonimidamideChiralPak IC, 2*25 cm, 5 um 15% EtOH in Hex 498.2 195 161b or 161a

(R)-or (S)- N′-((4-cyano-3-fluoro-2,6- diisopropylphenyl)carbamoyl)-4-(hydroxymethyl)-2-(2- hydroxypropan-2-yl)thiazole-5- sulfonimidamideChiralPak IC, 2*25 cm, 5 um 15% EtOH in Hex 498.2 196 165a or 165b

(S)-or (R)- N′-((4-cyano-2,6- diisopropylphenyl)carbamoyl)-4-(methylsulfonyl)benzene- sulfonimidamide ChiralPak IG, 2*25 cm, 5 um 30%EtOH in Hex (0.1% DEA) 463.1 197 165b or 165a

(R)-or (S)- N′-((4-cyano-2,6- diisopropylphenyl)carbamoyl)-4-(methylsulfonyl)benzene- sulfonimidamide ChiralPak IG, 2*25 cm, 5 um 30%EtOH in Hex (0.1% DEA) 463.1 198 172a or 172b

N′-((4-cyano-2,6- diisopropylphenyl)carbamoyl)-3,5-bis(2-hydroxypropan-2- yl)benzenesulfonimidamide ChiralPak IC, 2*25 cm,5 um 15% EtOH in Hex (0.1% DEA) 501.2 199 172b or 172a

N′-((4-cyano-2,6- diisopropylphenyl)carbamoyl)-3,5-bis(2-hydroxypropan-2- yl)benzenesulfonimidamide ChiralPak IC, 2*25 cm,5 um 15% EtOH in Hex (0.1% DEA) 501.2 200 106a or 106b

(R)-or (S)- N′-(8-fluoro-1,2,3,5,6,7-hexahydro-s-indacen-4-ylcarbamoyl)-2-(2- hydroxypropan-2-yl)thiazole-5-sulfonimidamide ChiralPak AD-H, 2*25 cm, 5 um 25% EtOH in CO2 439.2 201106b or 106a

(S)-or (R)- N′-(8-fluoro-1,2,3,5,6,7-hexahydro-s-indacen-4-ylcarbamoyl)-2-(2- hydroxypropan-2-yl)thiazole-5-sulfonimidamide ChiralPak AD-H, 2*25 cm, 5 um 25% EtOH in CO₂ 439.2 202136a or 136b

(S)-or (R)- N′-(1,2,3,5,6,7-hexahydro-s-indacen-4-ylcarbamoyl)-4-(2-hydroxypropan- 2-yl)furan-2-sulfonimidamide ChiralART Cellulose- SB, 2*25 cm, 5 um 20% EtOH in Hex (0.2% DEA) 404.2 203136b or 136a

(R)-or (S)- N′-(1,2,3,5,6,7-hexahydro-s-indacen-4-ylcarbamoyl)-4-(2-hydroxypropan- 2-yl)furan-2-sulfonimidamide ChiralART Cellulose- SB, 2*25 cm, 5 um 20% EtOH in Hex (0.2% DEA) 404.2 204183a or 183b

(R)-or (S)- N′-(1,2,3,5,6,7-hexahydro-s-indacen-4-ylcarbamoyl)-4-(2-hydroxypropan- 2-yl)thiophene-2-sulfonimidamideChiralPak ID, 2*25 cm, 5 um 20% EtOH in Hex (0.1% DEA) 418.1 (M − 1) 205183a or 183b

(S)-or (R)- N'-(1,2,3,5,6,7-hexahydro-s-indacen-4-ylcarbamoyl)-4-(2-hydroxypropan- 2-yl)thiophene-2-sulfonimidamideChiralPak ID, 2*25 cm, 5 um 20% EtOH in Hex (0.1% DEA) 418.1 (M − 1) 206176a or 176b

(S)-or (R)- N′-(8-fluoro-1,2,3,5,6,7-hexahydro-s-indacen-4-ylcarbamoyl)-4-(2- hydroxypropan-2-yl)thiophene-2-sulfonimidamide ChiralPak IG, 2*25 cm, 5 um 30% EtOH in Hex 438.2 207176b or 176a

(R)-or (S)- N′-(8-fluoro-1,2,3,5,6,7-hexahydro-s-indacen-4-ylcarbamoyl)-4-(2- hydroxypropan-2-yl)thiophene-2-sulfonimidamide ChiralPak IG, 2*25 cm, 5 um 30% EtOH in Hex 438.2

Example 77

MS-ESI: 421.1 (M+1). ¹H NMR (400 MHz, DMSO-d₆) δ 8.41 (br s, 1H), 7.74(br s, 2H), 7.68 (s, 1H), 6.87 (s, 1H), 5.36 (s, 1H), 3.02-2.50 (m, 8H),2.10-1.80 (m, 4H), 1.48 (s, 6H).

Example 200

MS-ESI: 439.2 (M+1). 1H NMR (400 MHz, DMSO-d₆) δ 8.38 (br, 1H), 8.02 (s,1H), 7.75 (br, 1H), 6.27 (s, 1H), 2.81 (t, J=7.6 Hz, 4H), 2.70 (t, J=6.8Hz, 4H), 2.02-1.95 (m, 4H), 1.50 (s, 6H).

Example 203

MS-ESI: 404.2 (M+1). ¹H NMR (300 MHz, DMSO-d₆) δ 8.42 (br s, 1H), 7.76(s, 1H), 7.72 (s, 2H), 7.01 (s, 1H), 6.88 (s, 1H), 5.11 (s, 1H),2.90-2.72 (m, 4H), 2.72-2.60 (m, 4H), 2.10-1.80 (m, 4H), 1.46 (s, 6H).

Example 205

MS-ESI: 418.1 (M−1). ¹H NMR (400 MHz, DMSO-d₆) δ 8.39 (br s, 1H), 7.68(s, 2H), 7.63 (s, 1H), 7.59 (s, 1H), 6.88 (s, 1H), 5.23 (s, 1H),2.95-2.75 (m, 4H), 2.75-2.60 (m, 4H), 2.05-1.80 (m, 4H), 1.43 (s, 6H).

Example 206

MS-ESI: 438.2 (M+1). ¹H NMR (300 MHz, DMSO-d₆) δ 8.41 (br s, 1H), 7.65(s, 2H), 7.59 (s, 1H), 7.55 (s, 1H), 5.20 (s, 1H), 2.90-2.60 (m, 8H),2.10-1.80 (m, 4H), 1.39 (s, 6H).

Example 208 (Compound 221)

4,5-Dichloro-N′-((4-fluoro-2,6-diisopropylphenyl)carbamoyl)thiophene-2-sulfonimidamide

Step 1: N-(tert-butyldimethylsilyl)-4,5-dichlorothiophene-2-sulfonamide

4,5-Dichlorothiophene-2-sulfonamide (50 mg, 0.22 mmol) was dissolved inanhydrous CH₂C₁₂ (2 mL). Triethylamine (0.090 mL, 0.65 mmol) and TBSCl(38 mg, 0.25 mmol) were added and the resulting mixture was stirredovernight at room temperature, or until the reaction was complete asindicated by LCMS (Method F: m/Z=424.1 [M+DMSO+H]⁺, retention time=3.70min). The reaction mixture was used in the next step as is.

Step 2:N-(tert-butyldimethylsilyl)-4,5-dichlorothiophene-2-sulfonimidamide

In an oven-dried vial under nitrogen, a solution of PPh₃Cl₂ (143 mg,0.44 mmol) was prepared in dichloroethane (1.5 mL). Triethylamine (0.120mL, 0.86 mmol) was introduced in a steady stream via syringe at 0° C.The reaction mixture was stirred at room temperature for 10 min. Thereaction mixture was then cooled in an ice/water bath for 2 min and thereaction mixture of TBS protected sulfonamide (prepared in 2 mL DCM)from step 1 was introduced via syringe rapidly drop by drop (additiontime <30 seconds). The resulting mixture was stirred at 0° C. for 30min, at which time anhydrous ammonia was bubbled into the reactionmixture for 45 seconds. The suspension thus formed was stirred in anice/water bath for 30 min and then warmed to room temperature andcentrifuged to remove solids. The supernatant was concentrated in vacuoand dried under high vacuum for 30 min.

Step 3:4,5-Dichloro-N′-((4-fluoro-2,6-diisopropylphenyl)carbamoyl)thiophene-2-sulfonimidamideandN-(tert-butyldimethylsilyl)-4,5-dichloro-N′-((4-fluoro-2,6-diisopropylphenyl)carbamoyl)thiophene-2-sulfonimidamide

To the crude reaction mixture from step 2 was added anhydrous THF (1.5mL) and the resulting solution was stirred in an ice/water bath for 5min, at which time NaH (17 mg, 0.44 mmol) was added. After 2 minstirring, a solution of 5-fluoro-2-isocyanato-1,3-diisopropylbenzene(36.5 mg, 0.165 mmol) in THF (3 ml) was added dropwise at 0° C. Theresulting mixture was brought to room temperature and stirred for 30 minto give a mixture of crude products. LC-MS (Method F): m/Z=451.8 [M+H]⁺,retention time=6.18 min; for TBS-protected product, 566.4 [M+H]⁺,retention time=9.25 min.

Step 4:4,5-Dichloro-N′-((4-fluoro-2,6-diisopropylphenyl)carbamoyl)thiophene-2-sulfonimidamide

To the reaction mixture from step 3 was carefully added 4N HCl indioxane (0.3 mL) and the resulting mixture was stirred at roomtemperature for approximately 30 min until the completion of reaction,as determined by LCMS analysis (Method F: 451.8 [M+H]⁺, retentiontime=6.18 min). The reaction mixture was then concentrated in vacuo.DMSO (0.5 mL) was added to the residue and the resulting solution waspurified on a prep-HPLC to afford the title compound. LC-MS: 451 [M+H]⁺.

TABLE 20 Examples in the following table were prepared using similarprocedures as described in Example 208 above starting from appropriatesulfonamides. Example Final Target Exact Mass # Number Structure IUPACName [M + H]⁺ 209 219

N′-((4-fluoro-2,6- diisopropylphenyl)carbamoyl)-1,3-dimethyl-1H-pyrazole-4- sulfonimidamide 396.05 210 217

N′-((4-fluoro-2,6- diisopropylphenyl)carbamoyl)naphthalene-2-sulfonimidamide 428.17 211 216

N′-((4-fluoro-2,6- diisopropylphenyl)carbamoyl)-2,3-dihydrobenzofuran-5- sulfonimidamide 420.07 212 215

N′-((4-fluoro-2,6- diisopropylphenyl)carbamoyl)-[1,1′-biphenyl]-2-sulfonimidamide 454.28 213 218

N′-((4-fluoro-2,6- diisopropylphenyl)carbamoyl)- 2-(methoxymethyl)benzenesulfonimidamide 422.17 214 214

2,5-dichloro-N′-((4-fluoro-2,6- diisopropylphenyl)carbamoyl)thiophene-3- sulfonimidamide 452.18 215 211

N′-((4-fluoro-2,6- diisopropylphenyl) carbamoyl)pyridine-3-sulfonimidamide 379.24 216 210

N′-((4-fluoro-2,6- diisopropylphenyl)carbamoyl) benzo[d][1,3]dioxole-5-sulfonimidamide 422.17 217 201

N′-((4-fluoro-2,6- diisopropylphenyl) carbamoyl)-2,5-dimethylfuran-3-sulfonimidamide 396.40 218 200

N′-((4-fluoro-2,6- diisopropylphenyl) carbamoyl)quinoline-3-sulfonimidamide 429.40 219 199

N′-((4-fluoro-2,6- diisopropylphenyl)carbamoyl)-6,7-dihydro-5H-pyrrolo[1,2- a]imidazole-3-sulfonimidamide 408.40 220 198

N′-((4-fluoro-2,6- diisopropylphenyl)carbamoyl)- 5-methylpyridine-2-sulfonimidamide 393.40

Example 221 (Compound 141)

N′-((1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-yl)carbamoyl)-4-(2-hydroxypropan-2-yl)-5-methylfuran-2-sulfonimidamide(Scheme 31)

Step 1: Phenyl(1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-yl)carbamate

Into a 50-mL 3-necked round-bottom flask purged and maintained withnitrogen, was placed1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-amine (50 mg, 0.29 mmol)in THF (10 mL), to this was added NaH (60% wt. oil dispersion, 22.8 mg,0.57 mmol) at 0° C.; and then phenyl chloroformate (67.4 mg, 0.43 mmol,)in THF (2.0 mL) was added dropwise at 0° C. The resulting solution wasstirred for 2 h at RT. This reaction solution was used for next stepdirectly without any purification.

Step 2:N-(tert-butyldimethylsilyl)-N′-((1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-yl)carbamoyl)-4-(2-hydroxypropan-2-yl)-5-methylfuran-2-sulfonimidamide

Into a 50-mL 3-necked round-bottom flask purged and maintained withnitrogen, was placedN-(tert-butyldimethylsilyl)-4-(2-hydroxypropan-2-yl)-5-methylfuran-2-sulfonoimidamide(96 mg, 0.29 mmol) in THF (10 mL). To this was added NaH (60% wt. oildispersion, 23.2 mg, 0.58 mmol) at 0° C., followed by phenyl(1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-yl)carbamate (127 mg,0.43 mmol) crude in THF from via syringe rapidly drop by drop. Theresulting mixture was stirred for 16 h at RT. The reaction was thenquenched by the addition of 5.0 mL of water. The resulting solution wasextracted with 4×10 ml of ethyl acetate. The combined organic layerswere dried over anhydrous sodium sulfate and concentrated under vacuum.The residue was eluted from a silica gel column with ethylacetate/petroleum ether (1;1). This resulted in 50 mg (38.4%) of thetitle compound as an off-white solid. MS-ESI: 533 (M+1).

Step 3:N′-((1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-yl)carbamoyl)-4-(2-hydroxypropan-2-yl)-5-methylfuran-2-sulfonimidamide

Into a 50-mL round-bottom flask, was placedN-(tert-butyldimethylsilyl)-N′-((1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-yl)carbamoyl)-4-(2-hydroxypropan-2-yl)-5-methylfuran-2-sulfonimidamide(58 mg, 0.11 mmol) in THF (10 mL), to this was added TBAF (28.8 mg, 0.11mmol). The resulting solution was stirred for 1 h at RT. The resultingmixture was concentrated under vacuum. The residue was eluted from asilica gel column with DCM/MeOH (10:1). The crude product was furtherpurified by Prep-HPLC with the following conditions: Column: XBridgePrep OBD C18 Column 19*250 mm, 5 um; Mobile Phase A: water (10 mMNH₄HCO₃), Mobile Phase B: ACN; Flow rate: 25 mL/min; Gradient: 11% B to40% B in 7 min; UV 254/210 nm; Rt: 6 min. This resulted in 25 mg(54.87%) of Example 221 as a white solid. MS-ESI: 419 (M+1). ¹H NMR (400MHz, DMSO-d₆, ppm) δ: 8.82 (s, 1H), 7.65 (s, 2H), 6.90 (s, 1H), 5.03 (s,1H), 2.82-2.78 (m, 4H), 2.76-2.67 (m, 4H), 2.41 (s, 3H), 2.00-1.92 (m,4H), 1.39 (s, 6H).

TABLE 21 Examples in the following table were prepared using similarconditions as described in Example 221 and Scheme 31 from appropriatestarting materials. Exact Example Final Target Mass # Number StructureIUPAC Name [M + H]⁺ 222 140

N′-((3,5-diisopropylpyridin-4- yl)carbamoyl)-4-(2-hydroxypropan-2-yl)-5- methylfuran-2-sulfonimidamide 423

Example 223 (Compound 321)

2-(2-Hydroxypropan-2-yl)-N′-((2,4,5,6-tetrahydro-1H-cyclobuta[f]inden-3-yl)carbamoyl)thiazole-5-sulfonimidamide(Scheme 3A) Examples 224 and 225 (Compound 321b and 321a)

(R)- and(S)-2-(2-hydroxypropan-2-yl)-N′-((2,4,5,6-tetrahydro-1H-cyclobuta[f]inden-3-yl)carbamoyl)thiazole-5-sulfonimidamideRoute 1:

Step 1:Tert-butyl(2-(2-hydroxypropan-2-yl)-N-((2,4,5,6-tetrahydro-1H-cyclobuta[f]inden-3-yl)carbamoyl)thiazole-5-sulfonimidoyl)carbamate

Into a 100-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was placed tert-butylN-[amino[2-(2-hydroxypropan-2-yl)-1,3-thiazol-5-yl]oxo-λ⁶-sulfanylidene]carbamate(1.39 g, 4.32 mmol) in THF (50 mL). To this solution was added NaH (60%wt. oil dispersion, 518 mg, 13 mmol) at 0° C., followed by the additionof 3-isocyanato-2,4,5,6-tetrahydro-1H-cyclobuta[f]indene (800 mg, 4.32mmol) in THF (5.0 mL) dropwise at 0° C. The resulting solution wasstirred for 14 h at RT. The reaction was then quenched by the additionof 100 mL of water. The resulting solution was extracted with 3×50 mL ofDCM. The organic layers combined and dried over anhydrous Na₂SO₄, thenconcentrated. The residue was eluted from a silica gel column with ethylacetate/petroleum ether (1:5 to 1:1). This resulted in 2.0 g (91%) oftitle compound as a light yellow solid. MS-ESI: 507 (M+1).

Step 2:2-(2-Hydroxypropan-2-yl)-N′-((2,4,5,6-tetrahydro-1H-cyclobuta[f]inden-3-yl)carbamoyl)thiazole-5-sulfonimidamide

Into a 100-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was placedtert-butyl(2-(2-hydroxypropan-2-yl)-N-((2,4,5,6-tetrahydro-1H-cyclobuta[f]inden-3-yl)carbamoyl)thiazole-5-sulfonimidoyl)carbamate (2.2 g, 4.34 mmol) in dioxane (40mL). To this was added conc. HCl (8 mL, 12 M) dropwise at 0° C. Theresulting solution was stirred for 14 h at RT. The resulting solutionwas diluted with 100 mL of water. The resulting solution was extractedwith 3×50 mL of DCM. The organic layers combined and dried overanhydrous Na₂SO₄, then concentrated. The crude product was purified byHP-Flash with the following conditions: Column, C18 silica gel; mobilephase, ACN:H₂O=25:75 increasing to ACN:H₂O=55:45 within 25; Detector, UV254 nm. This resulted in 1.5 g (85%) of Example 223. MS-ESI: 407 (M+1).¹H NMR (300 MHz, DMSO-d₆) δ 8.35 (s, 1H), 8.05 (s, 1H), 7.74 (s, 2H),6.66 (s, 1H), 6.25 (s, 1H), 3.06-2.94 (m, 2H), 2.93-2.84 (m, 2H),2.82-2.60 (m, 4H), 2.03-1.79 (m, 2H), 1.50 (s, 6H).

Step 3: Chiral Resolution

Example 223 (1.5 g) was separated with the followed condition: Column:CHIRALPAK IG, 20*250 mm, 5 um; Mobile Phase A: CO₂: 60, Mobile Phase B:MeOH—Preparative: 40; Flow rate: 50 mL/min; 220 nm. The resultingsolution was stirred for 20 min at 10° C. This resulted in 546 mg (99%ee, 36.4%) of Example 224 (RT₁: 3.47 min) as a white solid and 595 mg(99% ee, 39.6%) of Example 225 (RT₂: 5.35 min) as a white solid. Theabsolute stereochemistry was tentatively assigned.

Example 224

MS-ESI: 407.1 (M+1). ¹H NMR (300 MHz, DMSO-d₆) δ 8.35 (s, 1H), 8.05 (s,1H), 7.74 (s, 2H), 6.66 (s, 1H), 6.25 (s, 1H), 3.06-2.94 (m, 2H),2.93-2.84 (m, 2H), 2.82-2.60 (m, 4H), 2.03-1.79 (m, 2H), 1.50 (s, 6H).

Example 225

MS-ESI: 407.1 (M+1). ¹H NMR (300 MHz, DMSO-d₆) δ 8.35 (s, 1H), 8.05 (s,1H), 7.74 (s, 2H), 6.66 (s, 1H), 6.25 (s, 1H), 3.06-2.94 (m, 2H),2.93-2.84 (m, 2H), 2.82-2.60 (m, 4H), 2.03-1.79 (m, 2H), 1.50 (s, 6H).

Route 2:

Step 1: Chiral resolution (R) and(S)-tert-butyl(amino(2-(2-hydroxypropan-2-yl)thiazol-5-yl)(oxo)-λ⁶-sulfaneylidene)carbamate

The product 10 g of Intermediate 28 was separated with the followedcondition: Column: CHIRALPAK IC, 5*25 cm, 5 um; Mobile Phase A:CO₂:55,Mobile Phase B: EtOH:HeX=1:1:45; Flow rate: 150 mL/min; UV 220 nm; 5.13(Intermediate 28A); Rte: 5.65 (Intermediate 28B). This resulted in 3 g(99.5% ee, 60%) of 28A, and 3 g (99.0% ee, 60%) of 28B.

Step 2: Tert-butyl(R)-(2-(2-hydroxypropan-2-yl)-N-((2,4,5,6-tetrahydro-1H-cyclobuta[f]inden-3-yl)carbamoyl)thiazole-5-sulfonimidoyl)carbamate

Into a 100-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was placed intermediate 28A (>99% ee, 1.67 g,5.20 mmol) in THF (50 mL), NaH (60% wt. oil dispersion, 624 mg, 15.6mmol) was added at 0° C., this was followed by the addition of3-isocyanato-2,4,5,6-tetrahydro-1H-cyclobuta[f]indene (850 mg, crude) inTHF (5 mL) dropwise at 0° C. The resulting solution was stirred for 14 hat RT. The reaction was then quenched by the addition of 100 mL ofwater. The resulting solution was extracted with 3×100 mL of DCM. Theorganic layers combined and dried over anhydrous Na₂SO₄, thenconcentrated. This resulted in 2.2 g (83.5%) of title compound as alight yellow solid. MS-ESI: 507 (M+1).

Step 3:(R)-2-(2-hydroxypropan-2-yl)-N′-((2,4,5,6-tetrahydro-1H-cyclobuta[f]inden-3-yl)carbamoyl)thiazole-5-sulfonimidamide

Into a 100-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was placed tert-butyl(S)-(2-(2-hydroxypropan-2-yl)-N-((2,4,5,6-tetrahydro-1H-cyclobuta[f]inden-3-yl)carbamoyl)thiazole-5-sulfonimidoyl)carbamate (2.2 g, 4.34 mmol) in dioxane (40mL), to this was added conc. HCl (8 mL, 12M) dropwise at 0° C. Theresulting solution was stirred for 8 h below 10° C. The resultingsolution was diluted with 100 mL of water. The resulting solution wasextracted with 3×100 mL of DCM. The organic layers combined and driedover anhydrous Na₂SO₄, then concentrated. The crude product was purifiedby HP-Flash with the following conditions: Column, C18 silica gel;mobile phase, MeCN:water=25:75 increasing to MeCN:water=55:45 within 30min; Detector, UV 210 nm. This resulted in 1.37 g (77.3%) of Example 224(99.4% ee) as a white solid. MS-ESI: 407 (M+1).

¹H NMR (300 MHz, DMSO-d₆) δ 8.43 (s, 1H), 8.09 (s, 1H), 7.90 (s, 2H),6.67 (s, 1H), 6.29 (s, 1H), 2.92 (d, J=3.9 Hz, 2H), 2.89 (d, J=3.9 Hz,2H), 2.90-2.55 (m, 4H), 2.00-1.75 (m, 6H), 1.50 (s, 6H).

TABLE 22 Examples in the following table were prepared using similarconditions as described in Example 223-Route 1 and Scheme 3A fromappropriate starting materials. Final Exact Example Target Mass # #Structure IUPAC Name [M + H]⁺ 226 329

2-(2-Hydroxypropan-2-yl)-N′- (tricyclo[6.2.0.03,6]deca-1,3(6),7-trien-2-ylcarbamoyl)thiazole-5- sulfonimidamide 393 227 375

N′-((1,2,3,5,6,7-hexahydro-s- indacen-4-yl-3,3,5,5- d₄)carbamoyl)-2-(2-hydroxypropan-2-yl)thiazole-5- sulfonimidamide 425 228 376

N′-((1,2,3,5,6,7-hexahydro-s- indacen-4-yl-1,1,7,7- d₄)carbamoyl)-2-(2-hydroxypropan-2-yl)thiazole-5- sulfonimidamide 425

Example 229 (Compound 307)

2-Fluoro-N′-((8-fluoro-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-hydroxybenzenesulfonimidamide(Scheme 3B)

Step 1:N-(tert-butyldimethylsilyl)-2-fluoro-N′-(8-fluoro-1,2,3,5,6,7-hexahydro-s-indacen-4-ylcarbamoyl)-4-methoxybenzenesulfonimidamide

Into a 50-mL round-bottom flask, was placed a solution ofN-(tert-butyldimethylsilyl)-2-fluoro-4-methoxybenzene-1-sulfonoimidamide(139 mg, 0.44 mmol) in THF (5.0 mL). To this solution was added NaH (60%wt. oil dispersion, 35.2 mg, 0.44 mmol) at 0° C. This was followed bythe addition of 4-fluoro-8-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene(95 mg, 0.44 mmol) in THF (5 mL) dropwise at RT. The resulting solutionwas stirred for 1 h at RT. The reaction was then quenched by theaddition of 100 mL of water. The resulting solution was extracted with3×50 mL of ethyl acetate. The organic layers combined and dried overanhydrous Na₂SO₄, and then concentrated. The residue was eluted from asilica gel column with ethyl acetate/petroleum ether (1:5 to 1:1). Thisresulted in 120 mg (51.2%) of the title compound as yellow oil. MS-ESI:536 (M+1).

Step 2:2-Fluoro-N′-(8-fluoro-1,2,3,5,6,7-hexahydro-s-indacen-4-ylcarbamoyl)-4-hydroxybenzenesulfonimidamide

Into a 50-mL round-bottom flask, was placed a solution of1-[[(tert-butyldimethylsilyl)imino](2-fluoro-4-methoxybenzene)sulfinyl]-3-(8-fluoro-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea(120 mg, 0.22 mmol) in ACN (5.0 mL), to this solution was added BBr₃(561 mg, 2.24 mmol) dropwise at 0° C. The resulting solution was stirredfor 2 h at RT. The reaction was then quenched by the addition of 5 mL ofMeOH. The resulting mixture was concentrated. The crude product (100 mg)was purified by Prep-HPLC under the following conditions: Column,XBridge Prep OBD C18, 19*250 mm, 5 um; mobile phase: water (10 mMNH₄HCO₃) and ACN (25% to 43% ACN gradient in 7 min); Detector, UV. Thisresulted in 17.7 mg (19.4%) of Example 229 as a white solid. MS-ESI: 408(M+1).

Example 230 (Compound 323)

N′((1-hydroxy-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(2-hydroxypropan-2-yl)thiazole-5-sulfonimidamide(Scheme 32)

Into a 50-mL round-bottom flask, was placed2-(2-hydroxypropan-2-yl)-N′-((1-oxo-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)thiazole-5-sulfonimidamide(100 mg, 0.23 mmol) in ethanol (10 mL). To this solution was added NaBH₄(17.4 mg, 0.46 mmol) in portions at 0° C. The resulting solution wasstirred for 2 h at RT. The crude product (5 mL) was purified byFlash-Prep-HPLC with the following conditions: Column: XBridge Prep OBDC18 Column 30×150 mm 5 um; Mobile Phase A: water (10 mM NH₄HCO₃), MobilePhase B: ACN; Flow rate: 60 mL/min; Gradient: 10% to 28% B in 7 min;210/254 nm; Rt: 6.00 min. This resulted in 180 mg of the title compound(Example 230) as a solid. MS-ESI: 437.1 (M+1).

¹H NMR (400 MHz, DMSO-d₆) δ 8.51 (br s, 1H), 8.04 (s, 1H), 7.82 (br s,2H), 6.97 (s, 1H), 6.28 (s, 1H), 5.07 (d, J=5.6 Hz, 1H), 5.05-4.85 (m,1H), 2.95-2.75 (m, 2H), 2.75-50 (m, 4H), 2.35-2.15 (m, 1H), 2.00-1.80(m, 2H), 1.80-1.60 (m, 1H), 1.51 (s, 6H).

Example 231 (Compound 338)

N′-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-((3-methoxyazetidin-1-yl)methyl)benzenesulfonimidamide(Scheme 33A)

Into a 50-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was placed1-[amino[4-(bromomethyl)phenyl]oxo-λ⁶-sulfanylidene]-3-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea(50 mg, 0.11 mmol) in THF (5 mL). To this solution was added DIEA (28.4mg, 0.22 mmol) and 3-methoxyazetidine (10.5 mg, 0.12 mmol) at RT. Theresulting solution was stirred for 1 h at 65° C. The resulting mixturewas concentrated. The crude product was purified by Prep-HPLC with thefollowing conditions: Column: XBridge Prep C18 OBD Column 19×100 mm 5 um13 nm; Mobile Phase A: water (10 mM NH₄HCO₃ mM+0.1% NH₃.H₂O), MobilePhase B: ACN; Flow rate: 25 mL/min; Gradient: 30% to 37% B in 9.5 min;254/210 nm; Rt: 9.62 min. This resulted in 5 mg of Example 231 as awhite solid. MS-ESI: 455 (M+1). ¹H NMR (300 MHz, DMSO-d₆) δ: 8.27 (br s,1H), 7.81 (d, J=8.4 Hz, 2H), 7.45 (d, J=8.4 Hz, 2H), 7.34 (s, 2H), 6.85(s, 1H), 4.02-3.94 (m, 1H), 3.67 (s, 2H), 3.51-3.46 (m, 2H), 3.14 (s,3H), 2.95-2.80 (m, 2H), 2.78-2.73 (m, 4H), 2.69-2.63 (m, 4H), 1.96-1.88(m, 4H).

TABLE 23 Examples in the following table were prepared using similarconditions as described in Example 231 and Scheme 33A from appropriatestarting materials. Final Exact Example Target Mass # # Structure IUPACName [M + H]⁺ 232 341

N′-(1,2,3,5,6,7-hexahydro-A- indacen-4-ylcarbamoyl)-4-(((2-methoxyethyl)(methyl)amino) methyl)benzenesulfonimidamide 457 233 342

N′-(1,2,3,5,6,7-hexahydro-s- indacen-4-ylcarbamoyl)-4-(hydroxymethyl)benzene- sulfonimidamide 386 234 345

N′-(1,2,3,5,6,7-hexahydro-s- indacen-4-ylcarbamoyl)-4-(morpholinomethyl)benzene- sulfonimidamide 455 235 346

4-((3,3-Difluoropyrrolidin-1- yl)methyl)-N′-(1,2,3,5,6,7-hexahydro-s-indacen-4- ylcarbamoyl)benzene- sulfonimidamide 475 236 347

N′-(1,2,3,5,6,7-hexahydro-s- indacen-4-ylcarbamoyl)-4-(pyrrolidin-1-ylmethyl) benzenesulfonimidamide 439 237 348

4-(Azetidin-1-ylmethyl)-N′- (1,2,3,5,6,7-hexahydro-s-indacen-4-ylcarbamoyl)benzene- sulfonimidamide 425 238 403

4-((Allyl(methyl)amino)methyl)- N′-(1,2,3,5,6,7-hexahydro-s-indacen-4-ylcarbamoyl)benzene- sulfonimidamide 439 239 402

N′-(1,2,3,5,6,7-hexahydro-s- indacen-4-ylcarbamoyl)-4-((methyl(prop-2-ynyl)amino) methyl)benzenesulfonimidamide 437 240 350

4- (((Cyclopropylmethyl)(methyl) amino)methyl)-N′-(1,2,3,5,6,7-hexahydro-s-indacen-4- ylcarbamoyl)benzene- sulfonimidamide 453 241 322

4-(((2,2- Difluoroethyl)(methyl)amino)methyl)-N′-(1,2,3,5,6,7-hexahydro- s-indacen-4-ylcarbamoyl)benzenesulfonimidamide 463 242 351

N′-(1,2,3,5,6,7-hexahydro-s- indacen-4-ylcarbamoyl)-4-(methoxymethyl)benzene- sulfonimidamide 400 243 358

4-(Aminomethyl)-N′-(1,2,3,5,6,7- hexahydro-s-indacen-4-ylcarbamoyl)benzene- sulfonimidamide 385

Example 244 (Compound 401)

N′-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-((2-oxopyrrolidin-1-yl)methyl)benzenesulfonimidamide(Scheme 33B)

Into a 40-mL sealed tube purged and maintained with an inert atmosphereof nitrogen, was placed1-[amino[4-(bromomethyl)phenyl]oxo-λ⁶-sulfanylidene]-3-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea(200 mg, 0.45 mmol) in THF (10 mL), to this stirred solution was addedDIEA (173 mg, 1.34 mmol) and pyrrolidin-2-one (114 mg, 1.34 mmol) at RT.The resulting solution was stirred for 3 h at 60° C. The resultingmixture was concentrated. The crude product was purified by Prep-HPLCwith the following conditions: Column, XBridge Prep OBD C18, 30×150 mm 5um; mobile phase, water (10 mM NH₄HCO₃) and ACN (25% to 44% ACN gradientin 7 min); Detector, UV. This resulted in 10 mg (4.95%) of Example 244as a white solid. MS-ESI: 453 (M+1).

¹H NMR (400 MHz, DMSO-d₆) δ: 8.26 (br s, 1H), 7.83 (d, J=8.0 Hz, 2H),7.40 (d, J=8.0 Hz, 2H), 7.27 (br s, 2H), 6.85 (s, 1H), 4.43 (s, 2H),3.26-3.22 (m, 2H), 2.78-2.74 (m, 4H), 2.65-2.61 (m, 4H), 2.30 (t, J=8.20Hz, 2H), 1.98-1.89 (m, 6H).

Example 245 (Compound 404)

N′-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-(2-hydroxypropan-2-yl)-N,N-dimethylthiophene-2-sulfonimidamide(Scheme 4A)

Into a 50-mL 3-necked round-bottom flask, was placed a solution of4-(2-hydroxypropan-2-yl)-N,N-dimethylthiophene-2-sulfonoimidamide (125mg, 0.50 mmol) in THF (2.0 mL). To this was added NaH (60% wt. oildispersion, 30.2 mg, 0.75 mmol) in several batches at 0° C. in anice/water bath. To the mixture was added4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (110 mg, 0.55 mmol) at 0°C. in an ice/water bath. The resulting solution was stirred for 30 minat 0° C. in a water/ice bath. The reaction was then quenched by theaddition of NH₄Cl (aq.). The resulting solution was extracted with ethylacetate and the organic layers combined, the organic layer was driedover anhydrous sodium sulfate and concentrated under vacuum. The crudeproduct was purified by Prep-HPLC with the following conditions: XBridge Prep C₁₈ OBD, 19*150 mm 5 um; mobile phase, water (10 mM NH₄HCO₃)and ACN (10% to 80% in 6 min); Detector, UV 254 nm. This resulted in 90mg (39.9%) of Example 245 as a white powder. MS-ESI: 448.2 (M+1). ¹H NMR(DMSO-d₆, 300 MHz): δ 8.60 (br s, 1H), 7.71 (s, 1H), 7.58 (br s, 1H),6.88 (s, 1H), 5.21 (s, 1H), 2.86-2.70 (m, 8H), 2.70 (s, 6H), 1.98-1.90(m, 4H), 1.3 (s, 6H).

Example 246 (Compound 331)

N′-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-(2-hydroxypropan-2-yl)-N-methylthiophene-2-sulfonimidamide(Scheme 4)

Into a 50-mL 3-necked round-bottom flask purged and maintained with aninert atmosphere of nitrogen, was placed4-(2-hydroxypropan-2-yl)-N-methylthiophene-2-sulfonoimidamide (106 mg,0.45 mmol) in THF (4.0 mL). This was followed by the addition of NaH(60% wt. oil dispersion, 23.5 mg, 0.59 mmol) in several batches at 0° C.in a water/ice bath. To this was added a solution of4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (99.1 mg, 0.50 mmol) inTHF (2.0 mL) dropwise with stirring at 0° C. The resulting solution wasstirred for 30 min at 0° C. in a water/ice bath. The reaction was thenquenched by the addition of water/ice. The resulting solution wasextracted with ethyl acetate and the organic layers combined, theorganic layer was dried over anhydrous sodium sulfate and concentratedunder vacuum. The crude product was purified by Prep-HPLC with thefollowing conditions: Column, X Bridge Shield RP18 OBD, 19×250 mm, 10um; mobile phase, water (10 mM NH₄HCO₃+0.1% NH₃.H₂O) and ACN (43% to 67%ACN gradient in 6 min); Detector, UV 254 nm. This resulted in 80 mg(40.79%) of Example 246 as a white solid. MS-ESI: 434.15 (M+1). ¹H NMR(DMSO-d₆, 300 MHz): δ 8.55 (br s, 1H) 7.65 (s, 1H), 7.59 (s, 1H), 7.53(s, 1H), 6.89 (s, 1H), 5.22 (s, 1H) 2.63-2.85 (m, 8H) 2.49 (s, 3H)2.00-1.80 (m, 4H) 1.31 (s, 6H).

TABLE 24 Examples in the following table were prepared using similarconditions as described in Example 246 and Scheme 4 from appropriatestarting materials. Final Exact Example Target Mass # Number StructureIUPAC Name [M + H]⁺ 247 339

N′-((1,2,3,5,6,7-hexahydro-s- indacen-4-yl)carbamoyl)-2-(2-hydroxypropan-2-yl)-N- methylthiazole-5-sulfonimidamide 435

Example 248 (Compound 405)

N′-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)(methyl)carbamoyl)-2-(2-hydroxypropan-2-yl)thiazole-5-sulfonimidamide(Scheme 34)

Step 1:Tert-butyl(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)(methyl)carbamoyl)-2-(2-hydroxypropan-2-yl)thiazole-5-sulfonimidoyl)carbamate

Into a 50-mL round-bottom flask, was placed tert-butylN-([[(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl]imino][2-(2-hydroxypropan-2-yl)-1,3-thiazol-5-yl]oxo-λ⁶-sulfanyl)carbamate(200 mg, 0.38 mmol) in THF (10 mL), to this stirred solution was addedCH₃I (60 mg, 0.42 mmol) dropwise at 0° C. The resulting solution wasstirred for 1 d at RT. The resulting mixture was concentrated. Thisresulted in 100 mg (49%) of the title compound as a solid. MS-ESI: 535(M+1).

Step 2:N′-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)(methyl)carbamoyl)-2-(2-hydroxypropan-2-yl)thiazole-5-sulfonimidamide

Into a 25-mL round-bottom flask, was placed tert-butylN-([[(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)(methyl)carbamoyl]imino][2-(2-hydroxypropan-2-yl)-1,3-thiazol-5-yl]oxo-λ⁶-sulfanyl)carbamate(100 mg) in HCl (4M, 10 mL). The resulting solution was stirred for 5 hat RT. The crude product was purified by Prep-HPLC with the followingconditions: Column, XBridge Prep C18 OBD, 5 um, 19*150 mm; mobile phase,water (10 mM NH₄HCO₃ mM) and ACN (22% to 53% ACN gradient in 7 min);Detector, UV. This resulted in 15.7 mg of Example 248 as a solid.MS-ESI: 435 (M+1).

TABLE 25 Example 249 was isolated as a side product from the preparationof Example 248. Example Final Target Exact Mass # Number Structure IUPACName [M + H]⁺ 249 406

N′-((1,2,3,5,6,7-hexahydro- s-indacen-4- yl)(methyl)carbamoyl)-2-(2-hydroxypropan-2-yl)-N- methylthiazole-5- sulfonimidamide 449

Example 250 (Compound 324)

N—(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(2-hydroxypropan-2-yl)thiazole-5-sulfonimidoyl)acetamide(Scheme 35A)

Into a 50-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was placed a mixture ofN-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(2-hydroxypropan-2-yl)thiazole-5-sulfonimidamide(200 mg, 0.48 mmol) and TEA (96 mg, 0.96 mmol) in DCM (20 mL). To thestirred solution, AC₂O (74 mg, 0.72 mmol) was added dropwise at 0° C.The resulting solution was stirred overnight. Then 80 mg of the productwas obtained by Prep-HPLC with the following conditions: Column: XBridgePrep C18 OBD Column 19×150 mm 5 um; Mobile Phase A: water (10 mMNH₄HCO₃), Mobile Phase B: ACN; Flow rate: 25 mL/min; Gradient: 18% B to41% B in 7 min; 254/210 nm; Rt: 5.05 min, this resulted in 100 mg of theExample 250 as a white solid. MS-ESI: 462.14 (M+1). ¹H NMR (300 MHz,CD₃OD-d₄) δ: 8.11 (s, 1H), 6.89 (s, 1H), 2.92-2.69 (m, 8H), 2.09-2.01(m, 4H), 1.99 (s, 3H), 1.60 (d, J=2.3 Hz, 6H).

Example 251 (Compound 407)

methyl4-((4-(N′-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamidimidoyl)benzyl)(methyl)amino)-4-oxobutanoate(Scheme 35)

Into a 8-mL round-bottom flask, was placed a solution of1-[amino([4-[(methylamino)methyl]-phenyl])oxo-λ⁶-sulfanylidene]-3-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea(100 mg, 0.25 mmol), methyl 4-chloro-4-oxobutanoate (37.8 mg, 0.25 mmol)in DMF (10 mL), to this stirred solution was added HATU (191 mg, 0.50mmol) and DIEA (64.9 mg, 0.50 mmol). The resulting solution was stirredfor 20 min at RT. The crude product was purified by Prep-HPLC with thefollowing conditions: Column, XBridge Shield RP18 OBD, 19*250 mm, 10 um;mobile phase, water (10 mM NH₄HCO₃) and ACN (15% to 75% ACN gradient in7 min); Detector, UV 250 nm. This resulted in 4.2 mg (3.27%) of Example251 as a white solid. MS-ESI: 513 (M+1). ¹H NMR (300 MHz, CD₃OD-d₄) δ:8.02-7.94 (m, 2H), 7.49-7.41 (m, 2H), 6.89 (s, 1H), 4.68 (s, 2H), 3.68(s, 3H), 3.04 (s, 3H), 2.85-2.80 (m, 4H), 2.75-2.60 (m, 8H), 2.03-1.97(m, 4H).

Example 252 (Compound 410)

4-((4-(N′-(1,2,3,5,6,7-hexahydro-s-indacen-4-ylcarbamoyl)sulfamimidoyl)benzyl)(methyl)amino)-4-oxobutanoicacid

Into a 50-mL round-bottom flask, was placed a solution of methyl3-[([4-[amino([[(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl]imino])oxo-λ⁶-sulfanyl]phenyl]methyl)(methyl)-carbamoyl]propanoate(80 mg, 0.16 mmol) in THF (3.0 mL) and H₂O (3.0 mL), to the stirredsolution was added KOH (17.5 mg, 0.31 mmol). The resulting solution wasstirred for 120 min at RT. The crude product was purified by Prep-HPLCwith the following conditions: Column, XBridge Shield RP18 OBD, 19*250mm, 10 um; mobile phase, water (10 mM NH₄HCO₃) and ACN (15% to 75%gradient in 7 min); Detector, UV250 nm. This resulted in 39 mg (50%) ofExample 252 as a white solid. MS-ESI: 499 (M+1). ¹H-NMR (300 MHz,CD₃OD-d₄) δ: 8.10-7.80 (m, 2H), 7.55-7.30 (m, 2H), 6.89 (s, 1H), 4.68(s, 2H), 3.04 (s, 3H), 2.90-2.60 (m, 12H), 2.10-1.80 (m, 4H).

Example 253 (Compound 408)

(E)-N-(4-(N′-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamidimidoyl)benzyl)-N-methyloct-4-en-7-ynamide(Scheme 35)

Example 253 was prepared using similar conditions as described inExample 251 and Scheme 35 from3-(3-(but-3-ynyl)-3H-diazirin-3-yl)propanoic acid and Intermediate 67.MS-ESI: 519 (M+1)

TABLE 26 Examples in the following table were prepared using similarconditions as described in Example 4-route 1 and Scheme 2 fromappropriate starting materials. Final Exact Example Target Mass # NumberStructure IUPAC Name [M + H]⁺ 254 308

N′-((3-cyano-2,6- diisopropylphenyl)carbamoyl)- 5-(2-hydroxypropan-2-yl)thiophene-2-sulfonimidamide 449 255 311

N′-((6-ethyl-1-methyl-1H- indazol-7-yl)carbamoyl)-5-(2-hydroxypropan-2-yl)thiazole- 2-sulfonimidamide 423 256 312

N′-((6-ethyl-2-methyl-2H- indazol-7-yl)carbamoyl)-5-(2-hydroxypropan-2-yl)thiazole- 2-sulfonimidamide 423 257 327

5-(2-hydroxypropan-2-yl)- N′-((3,5,6,7-tetrahydro-2H-indeno[5,6-b]furan-4-yl) carbamoyl)thiazole-2- sulfonimidamide 423 258326

5-(2-Hydroxypropan-2-yl)- N′-((3,5,6,7-tetrahydro-2H-indeno[5,6-b]furan-8-yl) carbamoyl)thiazole-2- sulfonimidamide 423 259139

N′-((1,2,3,5,6,7-hexahydro- s-indacen-4-yl)carbamoyl)-5-(2-hydroxypropan-2-yl)-1- phenyl-1H-pyrazole-3- sulfonimidamide 480 260137

N′-((1,2,3,5,6,7-hexahydro- s-indacen-4-yl)carbamoyl)-6-(2-hydroxypropan-2-yl) pyridine-3-sulfonimidamide 415 261 409

N-(4-(N′-((1,2,3,5,6,7- hexahydro-s-indacen-4- yl)carbamoyl)sulfamidi-midoyl)benzyl)-N- methylpent-4-ynamide 479 262 303

4-(2-Hydroxypropan-2-yl)- N′-((2,4,5,6-tetrahydro-1H-cyclobuta[f]inden-3-yl) carbamoyl)thiazole-2- sulfonimidamide 407 263325

4-(2-Hydroxypropan-2-yl)- N′-((3,5,6,7-tetrahydro-2H-indeno[5,6-b]furan-8-yl) carbamoyl)thiazole-2- sulfonimidamide 423 264138

N′-((1,2,3,5,6,7-hexahydro- s-indacen-4-yl)carbamoyl)-6-(2-hydroxypropan-2-yl)- 2-methylpyridine-3- sulfonimidamide 429 265332

N′-(1,2,3,5,6,7-hexahydro- s-indacen-4-ylcarbamoyl)-4-(2-hydroxypropan-2-yl)- 5-methylthiazole-2- sulfonimidamide 435 266334

4-(1-(Dimethylamino)ethyl)- N′-(1,2,3,5,6,7-hexahydro-s-indacen-4-ylcarbamoyl) benzenesulfonimidamide 427 267 335

4-(2-(Dimethylamino)propan- 2-yl)-N′-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl- carbamoyl)benzene- sulfonimidamide 441 268 337

N-(4-(N′-(1,2,3,5,6,7- hexahydro-s-indacen-4- ylcarbamoyl)sulfamimidoyl)benzyl)-N-methylacetamide 441 269 113

3-Fluoro-N′-(1,2,3,5,6,7- hexahydro-s-indacen-4- ylcarbamoyl)-5-(2-hydroxypropan-2-yl) thiophene-2- sulfonimidamide 438 270 343

N′-((1,2,3,5,6,7-hexahydro- s-indacen-4-yl)carbamoyl)- 2-methyl-1,2,3,4-tetrahydroisoquinoline-6- sulfonimidamide 425 271 349

N-(1,2,3,5,6,7-hexahydro-s- indacen-4-ylcarbamoyl)-2- methyl-1,2,3,4-tetrahydroisoquinoline-7- sulfonimidamide 425 272 344

4-((Dimethylamino)methyl)- N′-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)- 2-methoxybenzene- sulfonimidamide 443 273 359

N′-(1,2,3,5,6,7-hexahydro- s-indacen-4-ylcarbamoyl)-1-methyl-1H-indazole-5- sulfonimidamide 410 274 352

N′-(1,2,3,5,6,7-hexahydro- s-indacen-4-ylcarbamoyl)-4-(2-methoxypropan-2-yl) benzenesulfonimidamide 428 275 354

N′-(1,2,3,5,6,7-hexahydro- s-indacen-4-ylcarbamoyl)-6-isobutylpyridine-3- sulfonimidamide 413 276 355

6-((Dimethylamino)methyl)- N′-(1,2,3,5,6,7-hexahydro-5-indacen-4-ylcarbamoyl) pyridine-3-sulfonimidamide 414 277 356

N′-(1,2,3,5,6,7-hexahydro-s- indacen-4-ylcarbamoyl)-4- isobutylbenzene-sulfonimidamide 412 278 357

5-((Dimethylamino)methyl)- N′-(1,2,3,5,6,7-hexahydro-s-indacen-4-ylcarbamoyl) pyridine-2-sulfonimidamide 414 279 340

5-((Dimethylamino)methyl)- 3-fluoro-N′-(1,2,3,5,6,7-hexahydro-s-indacen-4- ylcarbamoyl)thiophene-2- sulfonimidamide 437 280377

4-((dimethylmino)methyl)- 3-fluoro-N′- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl) benzenesulfonimidamide 431 281 378

3-fluoro-5-(2-hydroxy- propan-2-yl)-N′- ((2,4,5,6-tetrahydro-1H-cyclobuta[f]inden-3-yl) carbamoyl)thiophene-2- sulfonimidamide 424 282379

N′-((1,2,3,5,6,7-hexahydro- s-indacen-4-yl)carbamoyl)-4-isopropylthiophene-2- sulfonimidamide 404 283 380

N-((1,2,3,5,6,7-hexahydro- s-indacen-4-yl)carbamoyl)-4-(1-methylpyrrolidin-2- yl)benzenesulfonimidamide 439 284 353

N′-((3,5-diisopropyl-1- phenyl-1H-pyrazol-4-yl) carbamoyl)-4-(2-hydroxy-propan-2-yl)thiophene-2- sulfonimidamide 490 285 333

N′-((1,2,3,6,7,8-hexahydro- as-indacen-4-yl)carbamoyl)-2-(2-hydroxypropan-2-yl) thiazole-5-sulfonimidamide 421 287 382

2-fluoro-N′-((1,2,3,5,6,7- hexahydro-s-indacen-4-yl)carbamoyl)-4-((methylamino) methyl) benzenesulfonimidamide 417 288 383

N′-((1,2,3,5,6,7-hexahydro- s-indacen-4-yl)carbamoyl)-6-isopropylpyridine-3- sulfonimidamide 399

TABLE 27 Examples in the following table were prepared using similarconditions as described in Example 4-route 2 and Scheme 3 fromappropriate starting materials. Final Exact Example Target Mass # NumberStructure IUPAC Name [M + H]⁺ 289 315

2-(2-Hydroxypropan-2-yl)-N′- ((3,5,6,7-tetrahydro-2H-indeno[5,6-b]furan-8- yl)carbamoyl)thiazole-5- sulfonimidamide 423 290316

N′-((6-ethyl-1H-indazol-7- yl)carbamoyl)-2-(2-hydroxypropan-2-yl)thiazole- 5-sulfonimidamide 409 291 317

2-(2-Hydroxypropan-2-yl)- N′-((1-methyl-1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)thiazole-5- sulfonimidamide 435 292319

2-(2-Hydroxypropan-2-yl)- N′-((3-methyl-1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)thiazole-5- sulfonimidamide 435 293320

2-(2-Hydroxypropan-2-yl)- N′-((1-oxo-1,2,3,5,6,7- hexahydro-s-indacen-4-yl)carbamoyl)thiazole-5- sulfonimidamide 435 294 336

2-(2-Hydroxypropan-2-yl)- N′-((3-oxo-1,2,3,5,6,7- hexahydro-s-indacen-4-yl)carbamoyl)thiazole-5- sulfonimidamide 435 295 330

N′-((1,2,3,5,6,7-hexahydro- s-indacen-4-yl)carbamoyl)-2-(2-methoxypropan-2-yl) thiazole-5-sulfonimidamide 435

TABLE 28 Examples in the following table were obtained from chiral HPLCresolutions of racemic examples described above. The chiral column andeluents are listed in the table. As a convention, the faster-elutingenantiomer is always listed first in the table followed by theslower-eluting enantiomer of the pair. The symbol * at a chiral centerdenotes that this chiral center has been resolved and the absolutestereochemistry at that center has not been determined. For mixturescontained two chiral centers and if two columns are used for separatingthe four diastereomers, the individual isomers are listed in the orderof faster column 1/faster column 2; faster column 1/slower column 2;slower column 1/faster column 2; followed by slower column 1/slowercolumn 2. Final Tar- LC- get MS Ex. Num- [M + # ber Structure IUPAC NameColumn Eluents H]⁺ 296 364a

(R) or (S)-N′- ((1,2,3,5,6,7- hexahydro-s- indacen-4-yl) carbamoyl)-5-(2-hydroxy- propan-2-yl) thiazole-2- sulfonimi- damide CHIRAL- PAK IG2*25 cm (5 um) 50% MeOH (8 mM NH₃- MeOH) in CO₂ ^(#) 421 297 364b

(S) or (R)-N′- ((1,2,3,5,6,7- hexahydro-s- indacen-4-yl) carbamoyl)-5-(2-hydroxy- propan-2-yl) thiazole-2- sulfonimi- damide CHIRAL- PAK IG2*25 cm (5 um) 50% MeOH (8 mM NH₃• MeOH) in CO₂ 421 298 365a

(R) or (S)-N′- ((3-fluoro-2,6- diisopropyl- phenyl)carba- moyl)-2-(2-hydroxy- propan-2-yl) thiazole-5- sulfonimi- damide Chiralpak ID, 2*25cm, 5 um IPA in Hex: DCM = 5:1 443 299 365b

(S) or (R)-N′- ((3-fluoro-2,6- diisopropyl- phenyl)carba- moyl)-2-(2-hydroxy- propan-2-yl) thiazole-5- sulfonimi- damide Chiralpak ID, 2*25cm, 5 um IPA in Hex: DCM= 5:1 443 300 308a

(R) or (S)-N′- ((3-cyano-2,6- diisopropyl- phenyl)carba- moyl)-5-(2-hydroxy- propan-2-yl) thiophene-2- sulfonimi- damide CHIRAL- PAK IG,20*250 mm, 5 um 30% EtOH in Hex (0.1% DEA) 449 301 308b

(S) or (R)-N′- ((3-fluoro-2,6- diisopropyl- phenyl)carba- moyl)-2-(2-hydroxy- propan-2-yl) thiazole-5- sulfonimi- damide CHIRAL- PAK IG,20*250 mm, 5 um 30% EtOH in Hex (0.1% DEA) 449 126 195a

Two isomers of (S,S)-and (S,R)-or (R,S)-and (R,R) 4-(2- hydroxy-propan-2-yl)- 5-methyl- N′-((3-methyl- 1,2,3,5,6,7- hexahydro-s-indacen-4-yl) carbamoyl) furan-2- CHIRAL- ART Cellulose- SB, 2*25 cm, 5um MeOH (0.1% DEA); 1^(st) and 2^(nd) peaks 432 sulfonimi- damide 127195e

Two isomers of (R,S)-and (R,R)-or (S,S)-and (S,R) 4-(2- hydroxy-propan-2-yl)- 5-methyl-N′- ((3-methyl- 1,2,3,5,6,7- hexahydro-s-indacen-4- yl)carbamoyl) furan-2-sul- MeOH (0.1% DEA); 3^(rd) peak 432fonimidamide 302 195ba

(R,R) or (R,S) or (S,S) or (S,R)-4-(2- hydroxy- propan-2-yl)-5-methyl-N′- ((3-methyl- 1,2,3,5,6,7- hexahydro-s- indacen-4-yl)carbamoyl) furan-2- sulfonimi- Pheno- mene x Lux 5u Cellu- lose-4, AXIAPacked 2.12*25 cm, 5 um 40% MeOH in CO₂ 432 damide re- solved fromexample 127 303 195bb

(R,S) or (R,R) or (S,R) or (S,S)-4-(2- hydroxy- propan-2-yl)-5-methyl-N′- ((3-methyl- 1,2,3,5,6,7- hexahydro-s- indacen-4-yl)carbamoyl) furan-2- sulfonimi- Pheno- mene x Lux 5u Cellu- lose-4, AXIAPacked 2.12*25 cm, 5 um 40% MeOH in CO₂ 432 damide re- solved fromexample 127 123 207c

Two isomers of (R,S)- and (R,R) 4-(2- hydroxy- propan-2-yl)-5-methyl-N′- (1-methyl- 1,2,3,5,6,7- hexahydros- indacen-4-yl-carbamoyl) Chiral- Pak IC, 2*25 cm, 5 um 50% EtOH in MTBE; 1^(st) and2^(nd) peaks 432.2 furan-2- sulfonimi- damide 124 207aa

(S,S)-or (S,R)-4-(2- hydroxy- propan-2-yl)- 5-methyl-N′- (1-methyl-1,2,3,5,6,7- hexahydros- indacen-4-yl- carbamoyl) furan-2- sulfonimi-50% EtOH in MTBE; 3^(rd) peak 432.2 damide 125 207b

(S,R)-or (S,S)-4-(2- hydroxy- propan-2-yl)- 5-methyl-N′- (1-methyl-1,2,3,5,6,7- hexahydros- indacen-4-yl- carbamoyl) furan-2- sulfonimi-50% EtOH in MTBE; 4^(th) peak 432.2 damide 304 207a

(R,R) or (R,S)-4-(2- hydroxy- propan-2-yl)- 5-methyl-N′- ((3-methyl-1,2,3,5,6,7- hexahydro-s- indacen-4-yl) carbamoyl) furan-2- sulfonimi-CHIRAL- PAK IG, 20*250 mm, 5 um EtOH in Hex (0.1% FA) 432 damide;resolved from example 123 305 207bb

(R,S) or (R,R)-4-(2- hydroxy- propan-2-yl)- 5-methyl-N′- ((3-methyl-1,2,3,5,6,7- hexahydro-s- indacen-4-yl) carbamoyl) furan-2- sulfonimi-CHIRAL- PAK IG, 20*250 mm, 5 um EtOH in Hex (0.1% FA) 432 damide;resolved from example 123 306 366a

(R) or (S)-N′- ((1,2,3,5,6,7- hexahydro-s- indacen-4-yl) carbamoyl)-4-(2-hydroxy- propan-2-yl) thiazole-2- sulfonimi- damide CHIRAL- PAKAS-H, 2*25 cm (5 um) 35% IPA (2 mM NH₃- MeOH) in CO₂ 421 307 366b

(S) or (R)-N′- ((1,2,3,5,6,7- hexahydro-s- indacen-4-yl) carbamoyl)-4-(2-hydroxy- propan-2-yl) thiazole-2- sulfonimi- damide CHIRAL- PAKAS-H, 2*25 cm (5 um) 35% IPA (2 mM NH₃- MeOH) in CO₂ 421 308 139a

(S) or (R)-N′- ((1,2,3,5,6,7- hexahydro-s- indacen-4-yl) carbamoyl)-5-(2-hydroxy- propan-2-yl)- 1-phenyl-1H- pyrazole-3- sulfonimi- damideCHIRAL- PAK AS-H, 2*25 cm (5 um) EtOH in Hex (0.1% DEA) 480 309 139b

(R) or (S)-N′- ((1,2,3,5,6,7- hexahydro-s- indacen-4-yl) carbamoyl)-5-(2-hydroxy- propan-2-yl)- 1-phenyl-1H- pyrazole-3- sulfonimi- damideCHIRAL- PAK AS-H, 2*25 cm (5 um) EtOH in Hex (0.1% DEA) 480 310 367a

(R) or (S)-N′- ((8-fluoro- 1,2,3,5,6,7- hexahydro-s- indacen-4-yl)carbamoyl)- 4-(2-hydroxy- propan-2-yl) thiazole-2- sulfonimi- damideChiral- pak AS-H 2*25 cm (5 um) 35% IPA in CO₂ 439 311 367b

(S) or (R)-N′- ((8-fluoro- 1,2,3,5,6,7- hexahydro-s- indacen-4-yl)carbamoyl)- 4-(2-hydroxy- propan-2-yl) thiazole-2- sulfonimi- damideChiral- pak AS-H 2*25 cm (5 um) 35% IPA in CO₂ 439 312 409b

(S) or (R)-N- (4-(N′- ((1,2,3,5,6,7- hexahydro-s- indacen-4-yl)carbamoyl) sulfamidi- midoyl) benzyl)-N- CHIRAL ART Cellu- lose- SB,2*25 cm, 5 um EtOH in Hex (8 mM NH₃- MeOH) 479 methylpent- 4-ynamide 313409a

(R) or (S)-N- (4-(N′- ((1,2,3,5,6,7- hexahydro-s- indacen-4-yl)carbamoyl) sulfamidi- midoyl) benzyl)-N- CHIRAL ART Cellu- lose- SB,2*25 cm, 5 um EtOH in Hex (8 mM NH₃• MeOH) 479 methylpent- 4-ynamide 314369a

(S) or (R)-N′- ((1,2,3,5,6,7- hexahydro-s- indacen-4-yl) carbamoyl)-4-((methyl- amino)methyl) benzene- sulfonimi- damide Chiral- pak ID-2,2*25 cm, 5 um EtOH in Hex (8 mM NH₃• MeOH) 399 315 369b

(R) or (S)-N′- ((1,2,3,5,6,7- hexahydro-s- indacen-4-yl) carbamoyl)-4-((methyl- amino)methyl) benzene- sulfonimi- damide Chiral- pak ID-2,2*25 cm, 5 um EtOH in Hex (8 mM NH₃• MeOH) 399 316 159a

Two isomers of (R,R) or (R,S) or (S,S) or (S,R)-N′- ((4-cyano-3-fluoro-2,6- diisopropyl- phenyl) carbamoyl)- 2-(1,2-di- hydroxy-propan-2-yl) thiazole-5- CHIRAL ART Cellu- lose- SB, 2*25 cm, 5 um EtOHin Hex (0.1% FA) 1^(st) and 2^(nd) peak 484 sulfonimi- damide 317 159ab

(R,R) or (R,S) or (S,S) or (S,R)-N- ((4-cyano-3- fluoro-2,6-diisopropyl- phenyl) carbamoyl)- 2-(1,2-di- hydroxy- CHIRAL ART Cellu-lose- SB, 2*25 cm, 5 um EtOH in Hex (0.1% FA) 3^(rd) peak 484propan-2-yl) thiazole-5- sulfonimi- damide 318 159ba

(S,S) or (S,R) or (R,R) or (R,S)-N- ((4-cyano-3- fluoro-2,6-diisopropyl- phenyl) carbamoyl)- 2-(1,2-di- hydroxy- CHIRAL ART Cellu-lose- SB, 2*25 cm, 5 um EtOH in Hex (0.1% FA) 4^(th) peak 484propan-2-yl) thiazole-5- sulfonimi- damide 319 137a

(S) or (R)-N′- ((1,2,3,5,6,7- hexahydro-s- indacen-4-yl) carbamoyl)-6-(2-hydroxy- propan-2-yl) pyridine-3- sulfonimi- damide CHIRAL ARTCellu- lose- SB, 2*25 cm, 5 um EtOH in Hex (0.1% FA) 415 320 137b

(R) or (S)-N′- ((1,2,3,5,6,7- hexahydro-s- indacen-4-yl) carbamoyl)-6-(2-hydroxy- propan-2-yl) pyridine-3- sulfonimi- damide CHIRAL ARTCellu- lose- SB, 2*25 cm, 5 um EtOH in Hex (0.1% FA) 415 321 317ab

(S,S) or (S,R)-2-(2- hydroxy- propan-2-yl)- N′-((1- methyl- 1,2,3,5,6,7-hexahydro-s- indacen-4-yl) carbamoyl) thiazole-5- sulfonimi- 1^(st) and2^(nd) peak (two isomers) Faster-eluting on column 1: CHIRAL ARTCellulose-SB, 2*25 cm, 5 um, IPA in Hex (0.1% FA). Separated further oncolumn 2: 435 damide CHIRALPAK (from Exam- IE, EtOH in ple 291) MTBE(0.1% FA) to obtain single isomers. 322 317aa

(S,R) or (S,S)-2-(2- hydroxy- propan-2-yl)- N′-((1- methyl- 1,2,3,5,6,7-hexahydro-s- indacen-4-yl) carbamoyl) thiazole-5- sulfonimi- 435 damide(from Exam- ple 291) 323 317bb

(R,R) or (R,S)-2-(2- hydroxy- propan-2-yl)- N′-((1- methyl- 1,2,3,5,6,7-hexahydro-s- indacen-4-yl) carbamoyl) thiazole-5- sulfonimi- CHIRAL ARTCellu- lose- SB, 2*25 cm, 5 um IPA in Hex (0.1% FA) 3^(rd) peak 435damide (from Exam- ple 291) 324 317ba

(R,S) or (R,R)-2-(2- hydroxy- propan-2-yl)- N′-((1- methyl- 1,2,3,5,6,7-hexahydro-s- indacen-4-yl) carbamoyl) thiazole-5- sulfonimi- IPA in Hex(0.1% FA) 4^(th) peak 435 damide (from Exam- ple 291) 325 316a

(S) or (R)-N′- ((6-ethyl-1H- indazol-7-yl) carbamoyl)- 2-(2-hydroxy-propan-2-yl) thiazole-5- sulfonimi- damide Chiral- pak ID, 2*25 cm, 5 umEtOH in Hex (0.1% FA) 409 326 316b

(R) or (S)-N′- ((6-ethyl-1H- indazol-7-yl) carbamoyl)- 2-(2-hydroxy-propan-2-yl) thiazole-5- sulfonimi- damide Chiral- pak ID, 2*25 cm, 5 umEtOH in Hex (0.1% FA) 409 327 373a

(S) or (R)-N′- ((6-ethyl-1- methyl-1H- indazol-7-yl) carbamoyl)-5-(2-hydroxy- propan-2-yl) thiazole-2- sulfonimi- damide CHIRAL- PAK IG,20*250 mm, 5 um EtOH in Hex (0.1% FA) 423 328 373b

(R) or (S)-N′- ((6-ethyl-1- methyl-1H- indazol-7-yl) carbamoyl)-5-(2-hydroxy- propan-2-yl) thiazole-2- sulfonimi- damide CHIRAL- PAK IG,20*250 mm, 5 um EtOH in Hex (0.1% FA) 423 329 374a

(S) or (R)-N′- ((6-ethyl-2- methyl-2H- indazol-7-yl) carbamoyl)-5-(2-hydroxy- propan-2-yl) thiazole-2- sulfonimi- damide CHIRAL ARTCellu- lose-SB S-5 um, 250*20 mm EtOH in Hex (0.1% FA) 423 330 374b

(R) or (S)-N′- ((6-ethyl-2- methyl-2H- indazol-7-yl) carbamoyl)-5-(2-hydroxy- propan-2-yl) thiazole-2- sulfonimi- damide CHIRAL ARTCellu- lose-SB S-5 um, 250*20 mm EtOH in Hex (0.1% FA) 423 331 319ab

(S,S) or (S,R)-2-(2- hydroxy- propan-2-yl)- N′-((3- methyl- 1,2,3,5,6,7-hexahydro-s- indacen-4-yl) carbamoyl) thiazole-5- sulfonimi- 1^(st) peakCHIRAL ART Cellu- lose- SB, 2*25 cm, 5 um EtOH in Hex (0.1% FA) 435damide 332 319aa

(R,R) or (R,S)-2-(2- hydroxy- propan-2-yl)- N′-((3- methyl- 1,2,3,5,6,7-hexahydro-s- indacen-4-yl) carbamoyl) thiazole-5- sulfonimi- 2^(nd) peakCHIRAL ART Cellu- lose- SB, 2*25 cm, 5 um EtOH in Hex (0.1% FA) 435damide 333 319bb

(S,R) or (S,S)-2-(2- hydroxy- propan-2-yl)- N′-((3- methyl- 1,2,3,5,6,7-hexahydro-s- indacen-4-yl) carbamoyl) thiazole-5- sulfonimi- 3^(rd) peakCHIRAL ART Cellu- lose- SB, 2*25 cm, 5 um EtOH in Hex (0.1% FA) 435damide 334 319ba

(R,S) or (R,R)-2-(2- hydroxy- propan-2-yl)- N′-((3- methyl- 1,2,3,5,6,7-hexahydro-s- indacen-4-yl) carbamoyl) thiazole-5- sulfonimi- 4^(th) peakCHIRAL ART Cellu- lose- SB, 2*25 cm, 5 um EtOH in Hex (0.1% FA) 435damide 335 320a

(S) or (R)-2-(2- Hydroxy- propan-2-yl)- N′-((1-oxo- 1,2,3,5,6,7-hexahydro-s- indacen-4-yl) carbamoyl) thiazole-5- sulfonimi- damide fromChiral- pak IA, 2*25 cm, 5 um EtOH in Hex (0.1% FA) 435 Example 293 336320b

(R) or (S)-2-(2- Hydroxy- propan-2-yl)- N′-((1-oxo- 1,2,3,5,6,7-hexahydro-s- indacen-4-yl) carbamoyl) thiazole-5- sulfonimi- damide fromChiral- pak IA, 2*25 cm, 5 um EtOH in Hex (0.1% FA) 435 Example 293 337323ab

(R,R) or (R,S)-N′- ((1-hydroxy- 1,2,3,5,6,7- hexahydro-s- indacen-4-yl)carbamoyl)- 2-(2-hydroxy- propan-2-yl) thiazole-5- sulfonimi- damide(from example 336) CHIRAL- PAK AD, 2*25 cm, 5 um EtOH (0.1% DEA) in CO₂,1^(st) peak 437 338 323bb

(R,S) or (R,R)-N′- ((1-hydroxy- 1,2,3,5,6,7- hexahydro-s- indacen-4-yl)carbamoyl)- 2-(2-hydroxy- propan-2-yl) thiazole-5- sulfonimi- damide(from example 336) EtOH (0.1% DEA) in CO₂, 2^(nd) peak 437 339 323aa

(S,S) or (S,R)-N′- ((1-hydroxy- 1,2,3,5,6,7- hexahydro-s- indacen-4-yl)carbamoyl)- 2-(2-hydroxy- propan-2-yl) thiazole-5- sulfonimi- damide(from example 335) CHIRAL- PAK AD, 2*25 cm, 5 um EtOH (0.1% DEA) in CO₂,1^(st) peak 437 340 323ba

(S,R) or (S,S)-N′- ((1-hydroxy- 1,2,3,5,6,7- hexahydro-s- indacen-4-yl)carbamoyl)- 2-(2-hydroxy- propan-2-yl) thiazole-5- sulfonimi- damide(from example 335) EtOH (0.1% DEA) in CO₂, 2^(nd) peak 437 341 303a

(R) or (S)- 4-(2-hydroxy- propan-2-yl)- N′-((2,4,5,6- tetrahydro-1H-cyclobuta [f]inden-3-yl) carbamoyl) thiazole-2- sulfonimi- damideChiral- pak ID, 2*25 cm, 5 um EtOH in Hex (0.1% FA) 407 342 303b

(R) or (S)- 4-(2-hydroxy- propan-2-yl)- N′-((2,4,5,6- tetrahydro-1H-cyclobuta [f]inden-3-yl) carbamoyl) thiazole-2- sulfonimi- damideChiral- pak ID, 2*25 cm, 5 um EtOH in Hex (0.1% FA) 407 343 315a

(R) or (S)- 2-(2-hydroxy- propan-2-yl)- N′-((3,5,6,7- tetrahydro-2H-indeno [5,6-b]furan- 8-yl) carbamoyl) thiazole-5- sulfonimi- damideChiral- pak ID, 2*25 cm, 5 um EtOH in Hex (0.1% FA) 423 344 315b

(R) or (S)- 2-(2-hydroxy- propan-2-yl)- N′-((3,5,6,7- tetrahydro-2H-indeno [5,6-b]furan- 8-yl) carbamoyl) thiazole-5- sulfonimi- damideChiral- pak ID, 2*25 cm, 5 um EtOH in Hex (0.1% FA) 423 345 138a

(R) or (S)- N′- ((1,2,3,5,6,7- hexahydro-s- indacen-4-yl) carbamoyl)-6-(2-hydroxy- propan-2-yl)- 2-methyl- pyridine-3- sulfonimi- damideCHIRAL- PAK IF, 2*25 cm, 5 um EtOH in Hex (8 mM NH₃- MeOH) 429 346 138b

(R) or (S)- N′- ((1,2,3,5,6,7- hexahydro-s- indacen-4-yl) carbamoyl)-6-(2-hydroxy- propan-2-yl)- 2-methyl- pyridine-3- sulfonimi- damideCHIRAL- PAK IF, 2*25 cm, 5 um EtOH in Hex (8 mM NH₃• MeOH) 429 347 328a

(R) or (S)- 5-(2-hydroxy- propan-2-yl)- N′-((3,5,6,7- tetrahydro-2H-indeno [5,6-b] furan-4-yl) carbamoyl) thiazole-2- sulfonimi- damideCHIRAL- PAK IC, 2*25 cm, 5 um EtOH in Hex (0.1% FA) 423 348 328b

(S) or (R)- 5-(2-hydroxy- propan-2-yl)- N′-((3,5,6,7- tetrahydro-2H-indeno [5,6-b] furan-4-yl) carbamoyl) thiazole-2- sulfonimi- damideCHIRAL- PAK IC, 2*25 cm, 5 um EtOH in Hex (0.1% FA) 423 349 326b

(S) or (R)- 5-(2-hydroxy- propan-2-yl)- N′-((3,5,6,7- tetrahydro-2H-indeno [5,6-b] furan-8-yl) carbamoyl) thiazole-2- sulfonimi- damideCHIRAL- PAK IG, 20*250 mm, 5 um IPA in Hex: DCM = 5:1 (0.1% FA) 423 350326a

(R) or (S)- 5-(2-hydroxy- propan-2-yl)- N′-((3,5,6,7- tetrahydro-2H-indeno [5,6-b] furan-8-yl) carbamoyl) thiazole-2- sulfonimi- damideCHIRAL- PAK IG, 20*250 mm, 5 um 423 351 318a

(S) or (R)- N′-((8- bromo- 1,2,3,5,6,7- hexahydro-s- indacen-4-yl)carbamoyl)- 5-(2-hydroxy- propan-2-yl) thiazole-2- sulfonimi- damideCHIRAL ART Cellu- lose- SB S- 5 um, 2*25 cm, 5 um EtOH in Hex (8 mM NH₃•MeOH) 499 352 318b

(R) or (S)- N′-((8- bromo- 1,2,3,5,6,7- hexahydro-s- indacen-4-yl)carbamoyl)- 5-(2-hydroxy- propan-2-yl) thiazole-2- sulfonimi- damideCHIRAL ART Cellu- lose- SB S- 5 um, 2*25 cm, 5 um EtOH in Hex (8 mM NH₃•MeOH) 499 353 325a

(S) or (R)- 4-(2-hydroxy- propan-2-yl)- N′-((3,5,6,7- tetrahydro-2H-indeno [5,6-b] furan-8-yl) carbamoyl) thiazole-2- sulfonimi- damideCHIRAL ART Cellu- lose- SB, 2*25 cm, 5 um EtOH in Hex (0.1% FA) 423 354325b

(R) or (S)- 4-(2-hydroxy- propan-2-yl)- N′-((3,5,6,7- tetrahydro-2H-indeno [5,6-b] furan-8-yl) carbamoyl) thiazole-2- sulfonimi- damideCHIRAL ART Cellu- lose- SB, 2*25 cm, 5 um EtOH in Hex (0.1% FA) 423 355329a

(R) or (S)- 2-(2-hydroxy- propan-2-yl)- N′-(tricyclo [6.2.0.03,6]deca-1,3(6),7- trien-2-yl- carbamoyl) thiazole-5- sulfonimi- damideChiral- pak ID, 2*25 cm, 5 um IPA in Hex (0.1% FA) 393 356 329b

(S) or (R)- 2-(2-hydroxy- propan-2-yl)- N′-(tricyclo [6.2.0.03,6]deca-1,3(6),7- trien-2-yl- carbamoyl) thiazole-5- sulfonimi- damideChiral- pak ID, 2*25 cm, 5 um IPA in Hex (0.1% FA) 393 357 404b

(R) or (S)-N′- ((1,2,3,5,6,7- hexahydro-s- indacen-4-yl) carbamoyl)-4-(2-hydroxy- propan-2-yl)- N,N- dimethyl- thiophene-2- sulfonimi-damide CHIRAL- PAK IG, 20*250 mm, 5 um IPA in Hex: DCM = 3:1 (10 mM NH₃-MeOH) 448 358 404a

(S) or (R)-N′- ((1,2,3,5,6,7- hexahydro-s- indacen-4-yl) carbamoyl)-4-(2-hydroxy- propan-2-yl)- N,N- dimethyl- thiophene-2- sulfonimi-damide CHIRAL- PAK IG, 20*250 mm, 5 um IPA in Hex: DCM = 3:1 (10 mM NH₃-MeOH) 448 359 332a

(R) or (S)-N′- ((1,2,3,5,6,7- hexahydro-s- indacen-4-yl) carbamoyl)-4-(2-hydroxy- propan-2-yl)- 5-methyl- thiazole-2- sulfonimi- damideChiral- pak ID, 2*25 cm, 5 um IPA in Hex (0.1% FA) 435 360 332b

(S) or (R)-N′- ((1,2,3,5,6,7- hexahydro-s- indacen-4-yl) carbamoyl)-4-(2-hydroxy- propan-2-yl)- 5-methyl- thiazole-2- sulfonimi- damideChiral- pak ID, 2*25 cm, 5 um IPA in Hex (0.1% FA) 435 361 335a

(R) or (S)-4-(2- (dimethyl- amino) propan-2- yl)-N′- ((1,2,3,5,6,7-hexahydro-s- indacen-4-yl) carbamoyl) benzene- sulfonimi- CHIRAL- PAKIG, 2.0*25 cm (5 um) IPA in Hex (8 mM NH₃- MeOH) 441 damide 362 335b

(S) or (R)-4-(2- (dimethyl- amino) propan-2- yl)-N′- ((1,2,3,5,6,7-hexahydro-s- indacen-4-yl) carbamoyl) benzene- sulfonimi- CHIRAL- PAKIG, 2.0*25 cm (5 um) IPA in Hex (8 mM NH₃- MeOH) 441 damide 363 336a

(S) or (R)-2-(2- Hydroxy- propan-2-yl)- N′-((3-oxo- 1,2,3,5,6,7-hexahydro-s- indacen-4-yl) carbamoyl) thiazole-5- sulfonimi- damideCHIRAL ART Cellu- lose- SB, 2*25 cm, 5 um EtOH in MTBE (10 mM NH₃- MeOH)435 364 336b

(R) or (S)-2-(2- Hydroxy- propan-2-yl)- N′-((3-oxo- 1,2,3,5,6,7-hexahydro-s- indacen-4-yl) carbamoyl) thiazole-5- sulfonimi- damideCHIRAL ART Cellu- lose- SB, 2*25 cm, 5 um EtOH in MTBE (10 mM NH₃- MeOH)435 365 337a

(S) or (R)-N- (4-(N′- ((1,2,3,5,6,7- hexahydro-s- indacen-4-yl)carbamoyl) sulfamidimi- doyl)benzyl)- N-methyl- acetamide CHIRAL ARTCellu- lose- SB, 2*25 cm, 5 um EtOH in Hex (8 mM NH₃- MeOH) 441 366 337b

(R) or (S)-N- (4-(N′- ((1,2,3,5,6,7- hexahydro-s- indacen-4-yl)carbamoyl) sulfamidimi- doyl)benzyl)- N-methyl- acetamide CHIRAL ARTCellu- lose- SB, 2*25 cm, 5 um EtOH in Hex (8 mM NH₃- MeOH) 441 367 371a

(S) or (R)-N- (3-(N′- ((1,2,3,5,6,7- hexahydro-s- indacen-4-yl)carbamoyl) sulfamidimi- doyl)benzyl)- N-methyl- acetamide CHIRAL ARTCellu- lose- SB, 2*25 cm, 5 um EtOH in Hex (8 mM NH₃- MeOH) 441 368 371b

(R) or (S)-N- (3-(N′- ((1,2,3,5,6,7- hexahydro-s- indacen-4-yl)carbamoyl) sulfamidimi- doyl)benzyl)- N-methyl- acetamide CHIRAL ARTCellu- lose- SB, 2*25 cm, 5 um EtOH in Hex (8 mM NH₃- MeOH) 441 369 372a

(S,R/S) or (R,R/S)-N′- ((3-hydroxy- 1,2,3,5,6,7- hexahydro-s-indacen-4-yl) carbamoyl)- 2-(2-hydroxy- propan-2-yl) thiazole-5-sulfonimi- damide Obtained from Example 363 N/A 435 (M − 1) 370 372b

(R,R/S) or (S,R/S)-N′- ((3-hydroxy- 1,2,3,5,6,7- hexahydro-s-indacen-4-yl) carbamoyl)- 2-(2-hydroxy- propan-2-yl) thiazole-5-sulfonimi- damide Obtained from Example 364 N/A 435 (M − 1) 371 334a

(S) or (R)-4-(1- (dimethyl- amino) ethyl)-N′- ((1,2,3,5,6,7-hexahydro-s- indacen-4-yl) carbamoyl) benzene- sulfonimi- damide CHIRALART Cellu- lose- SB, 2*25 cm, 5 um IPA in Hex (8 mM NH₃- MeOH) 427 372334b

(R) or (S)-4-(1- (dimethyl- amino) ethyl)-N′- ((1,2,3,5,6,7-hexahydro-s- indacen-4-yl) carbamoyl) benzene- sulfonimi- damide CHIRALART Cellu- lose- SB, 2*25 cm, 5 um IPA in Hex (8 mM NH₃- MeOH) 427 373339a

(R) or (S)-N′- ((1,2,3,5,6,7- hexahydro-s- indacen-4-yl) carbamoyl)-2-(2-hydroxy- propan-2-yl)- N-methyl- thiazole-5- sulfonimi- damideCHIRAL- PAK IE, 2*25 cm, 5 um IPA in Hex (8 mM NH₃- MeOH) 435 374 339b

(S) or (R)-N′- ((1,2,3,5,6,7- hexahydro-s- indacen-4-yl) carbamoyl)-2-(2-hydroxy- propan-2-yl)- N-methyl- thiazole-5- sulfonimi- damideCHIRAL- PAK IE, 2*25 cm, 5 um IPA in Hex (8 mM NH₃- MeOH) 435 375 334ab

(S,R) or (S,S) or (R,S) or (R,R)-4- (1-(dimethyl- amino) ethyl)-N′-((1,2,3,5,6,7- hexahydro-s- indacen-4-yl) carbamoyl) benzene- CHIRAL-PAK IG, 20*250 mm, 5 um EtOH in Hex (8 mM NH₃- MeOH) 427 sulfonimi-damide 376 334aa

(S,S) or (S,R) or (R,R) or (R,S)-4- (1-(dimethyl- amino) ethyl)-N′-((1,2,3,5,6,7- hexahydro-s- indacen-4-yl) carbamoyl) benzene- CHIRAL-PAK IG, 20*250 mm, 5 um EtOH in Hex (8 mM NH₃- MeOH) 427 sulfonimi-damide 377 334bb

(R,R) or (R,S) or (S,S) or (S,R)-4- (1-(dimethyl- amino) ethyl)-N′-((1,2,3,5,6,7- hexahydro-s- indacen-4-yl) carbamoyl) benzene- CHIRAL-PAK IG, 20*250 mm, 5 um EtOH in Hex (8 mM NH₃- MeOH) 427 sulfonimi-damide 378 334ba

(R,S) or (R,R) or (S,R) or (S,S)-4- (1-(dimethyl- amino) ethyl)-N′-((1,2,3,5,6,7- hexahydro-s- indacen-4-yl) carbamoyl) benzene- CHIRAL-PAK IG, 20*250 mm, 5 um EtOH in Hex (8 mM NH₃- MeOH) 427 sulfonimi-damide 379 338a

(R) or (S)-N′- ((1,2,3,5,6,7- hexahydro-s- indacen-4-yl) carbamoyl)-4-((3- methoxy- azetidin-1-yl) methyl) benzene- sulfonimi- CHIRAL- PAKIF, 2*25 cm, 5 um EtOH in Hex (8 mM NH₃- MeOH) 455 damide 380 338b

(S) or (R)-N′- ((1,2,3,5,6,7- hexahydro-s- indacen-4-yl) carbamoyl)-4-((3- methoxy- azetidin-1-yl) methyl) benzene- sulfonimi- CHIRAL- PAKIF, 2*25 cm, 5 um EtOH in Hex (8 mM NH₃- MeOH) 455 damide 381 340a

(R) or (S)-5- ((dimethyl- amino) methyl)-3- fluoro-N′- ((1,2,3,5,6,7-hexahydro-s- indacen-4-yl) carbamoyl) thiophene-2- sulfonimi- damideCHIRAL- PAK IG, 20*250 mm, 5 um Hex (0.1% DEA): EtOH = 50:50 437 382340b

(S) or (R)-5- ((dimethyl- amino) methyl)-3- fluoro-N′- ((1,2,3,5,6,7-hexahydro-s- indacen-4-yl) carbamoyl) thiophene-2- sulfonimi- damideCHIRAL- PAK IG, 20*250 mm, 5 um Hex (0.1% DEA): EtOH = 50:50 437 383361b

(R) or (S)-4- ((dimethyl- amino) methyl)-N′- ((1,2,3,5,6,7- hexahydro-s-indacen-4-yl) carbamoyl)- N-methyl- benzene- sulfonimi- damide CHIRAL-PAK IE, 2*25 cm, 5 um EtOH in Hex (8 mM NH₃- MeOH) 427 384 361a

(S) or (R)-4- ((dimethyl- amino) methyl)-N′- ((1,2,3,5,6,7- hexahydro-s-indacen-4-yl) carbamoyl)- N-methyl- benzene- sulfonimi- damide CHIRAL-PAK IE, 2*25 cm, 5 um EtOH in Hex (8 mM NH₃- MeOH) 427 385 113a

(R) or (S)-3- fluoro-N′- ((1,2,3,5,6,7- hexahydro-s- indacen-4-yl)carbamoyl)- 5-(2-hydroxy- propan-2-yl) thiophene-2- sulfonimi- damideCHIRAL- PAK IG, 20*250 mm, 5 um IPA in Hex (8 mM NH₃- MeOH) 438 386 113b

(S) or (R)-3- fluoro-N′- ((1,2,3,5,6,7- hexahydro-s- indacen-4-yl)carbamoyl)- 5-(2-hydroxy- propan-2-yl) thiophene-2- sulfonimi- damideCHIRAL- PAK IG, 20*250 mm, 5 um IPA in Hex (8 mM NH₃- MeOH) 438 387 330a

(S) or (R)-N′- ((1,2,3,5,6,7- hexahydro-s- indacen-4-yl) carbamoyl)-2-(2- methoxy- propan-2-yl) thiazole-5- sulfonimi- damide CHIRAL ARTCellu- lose- SB, 2*25 cm, 5 um EtOH in Hex (8 mM NH₃- MeOH) 435 388 330b

(R) or (S)-N′- ((1,2,3,5,6,7- hexahydro-s- indacen-4-yl) carbamoyl)-2-(2- methoxy- propan-2-yl) thiazole-5- sulfonimi- damide CHIRAL ARTCellu- lose- SB, 2*25 cm, 5 um EtOH in Hex (8 mM NH₃- MeOH) 435 389 341a

(S) or (R)-N′- ((1,2,3,5,6,7- hexahydro-s- indacen-4-yl) carbamoyl)-4-(((2- methoxy- ethyl) (methyl) amino) methyl) CHIRAL- Cellu- lose-SB4.6*100 mm 3 um Hex (0.1% DEA): EtOH = 70:30 457 benzene- sulfonimi-damide 390 341b

(R) or (S)-N′- ((1,2,3,5,6,7- hexahydro-s- indacen-4-yl) carbamoyl)-4-(((2- methoxy- ethyl) (methyl) amino) methyl) CHIRAL- Cellu- lose-SB4.6*100 mm 3 um Hex (0.1% DEA): EtOH = 70:30 457 benzene- sulfonimi-damide 391 360ba

(R,R) or (R,S) or (S,S) or (S,R)-N′- ((3-hydroxy- 1,2,3,5,6,7-hexahydro-s- indacen-4-yl) carbamoyl)- 2-(2-hydroxy- propan-2-yl)thiazole-5- sulfonimi- damide (from CHIRAL- PAK IG, 20*250 mm, 5 um EtOHin MTBE (10 mM NH₃- MeOH) 437 Example 370) 392 360bb

(R,S) or (R,R) or (S,R) or (S,S)-N′- ((3-hydroxy- 1,2,3,5,6,7-hexahydro-s- indacen-4-yl) carbamoyl)- 2-(2-hydroxy- propan-2-yl)thiazole-5- sulfonimi- damide (from CHIRAL- PAK IG, 20*250 mm, 5 um EtOHin MTBE (10 mM NH₃- MeOH) 437 Example 370) 393 363b

(R)-N′- ((1,2,3,5,6,7- hexahydro-s- indacen-4-yl) carbamoyl)-2-(2-hydroxy- propan-2-yl- 1,1,1,3,3,3- d₆)thiazole- 5-sulfonimi- damideCHIRAL- PAK IF, 2*25 cm, 5 um 40% MeOH in CO₂ 427 394 363a

(S)-N′- ((1,2,3,5,6,7- hexahydro-s- indacen-4-yl) carbamoyl)-2-(2-hydroxy- propan-2-yl- 1,1,1,3,3,3- d₆)thiazole- 5-sulfonimi- damideCHIRAL- PAK IF, 2*25 cm, 5 um 40% MeOH in CO₂ 427 395 343a

(R) or (S)-N′- ((1,2,3,5,6,7- hexahydro-s- indacen-4-yl) carbamoyl)-2-methyl- 1,2,3,4- tetrahydro- isoquinoline- 6-sulfonimi- damide CHIRAL-PAK IG, 20*250 mm, 5 um EtOH in Hex (8 mM NH₃- MeOH 425 396 343b

(S) or (R)-N′- ((1,2,3,5,6,7- hexahydro-s- indacen-4-yl) carbamoyl)-2-methyl- 1,2,3,4- tetrahydro- isoquinoline- 6-sulfonimi- damide CHIRAL-PAK IG, 20*250 mm, 5 um EtOH in Hex (8 mM NH₃- MeOH 425 397 359a

(R) or (S)-N′- ((1,2,3,5,6,7- hexahydro-s- indacen-4-yl) carbamoyl)-1-methyl- 1H- indazole-5- sulfonimi- damide Chiral- pakID, 2*25 cm, 5 umIPA in Hex: DCM = 3:1 (10 mM NH₂- MeOH) 410 398 359b

(S) or (R)-N′- ((1,2,3,5,6,7- hexahydro-s- indacen-4-yl) carbamoyl)-1-methyl- 1H- indazole-5- sulfonimi- damide Chiral- pakID, 2*25 cm, 5 umIPA in Hex: DCM = 3:1 (10 mM NH₂- MeOH) 410 399 352a

(R) or (S)-N′- ((1,2,3,5,6,7- hexahydro-s- indacen-4-yl) carbamoyl)-4-(2- methoxy- propan-2-yl) benzene- sulfonimi- CHIRAL- PAK IG, 2.0*25cm (5 um) Hex (0.1% DEA): IPA = 70:30 428 damide 400 352b

(S) or (R)-N′- ((1,2,3,5,6,7- hexahydro-s- indacen-4-yl) carbamoyl)-4-(2- methoxy- propan-2-yl) benzene- sulfonimi- CHIRAL- PAK IG, 2.0*25cm (5 um) Hex (0.1% DEA): IPA = 70:30 428 damide 401 383a

(R) or (S)-N′- ((1,2,3,5,6,7- hexahydro-s- indacen-4-yl) carbamoyl)-6-isopropyl- pyridine-3- sulfonimi- damide CHIRAL- PAK IG, 2*25 cm, 5 umEtOH in Hex (8 mM NH₃- MeOH) 399 402 383b

(S) or (R)-N′- ((1,2,3,5,6,7- hexahydro-s- indacen-4-yl) carbamoyl)-6-isopropyl- pyridine-3- sulfonimi- damide CHIRAL- PAK IG, 2*25 cm, 5 umEtOH in Hex (8 mM NH₃- MeOH) 399 403 382a

(R) or (S)-2- fluoro-N′- ((1,2,3,5,6,7- hexahydro-s- indacen-4-yl)carbamoyl)- 4-((methyl- amino) methyl) benzene- sulfonimi- CHIRAL- PAKIG, 2*25 cm, 5 um EtOH in Hex (8 mM NH₃- MeOH) 417 damide 404 382b

(S) or (R)-2- fluoro-N′- ((1,2,3,5,6,7- hexahydro-s- indacen-4-yl)carbamoyl)- 4-((methyl- amino) methyl) benzene- sulfonimi- CHIRAL- PAKIG, 2*25 cm, 5 um EtOH in Hex (8 mM NH₃• MeOH) 417 damide 405 379a

(R) or (S)-N′- ((1,2,3,5,6,7- hexahydro-s- indacen-4-yl) carbamoyl)-4-isopropyl- thiophene-2- sulfonimi- damide CHIRAL- PAK IG, 2.0*25 cm (5um) EtOH in Hex (8 mM NH₃- MeOH) 404 406 379b

(S) or (R)-N′- ((1,2,3,5,6,7- hexahydro-s- indacen-4-yl) carbamoyl)-4-isopropyl- thiophene-2- sulfonimi- damide CHIRAL- PAK IG, 2.0*25 cm (5um) EtOH in Hex (8 mM NH₃- MeOH) 404 407 380a

(R,R) or (R,S) or (S,S) or (S,R)-N- ((1,2,3,5,6,7- hexahydro-s-indacen-4-yl) carbamoyl)- 4-(1-methyl- pyrrolidin-2- yl)benzene- CHIRAL-PAK IG, 20*250 mm, 5 um IPA in Hex: DCM = 5:1 (10 mM NH₃- MeOH) 439sulfonimi- damide 408 380b

(S,R) or (S,S) or (R,S) or (R,R)-N- ((1,2,3,5,6,7- hexahydro-s-indacen-4-yl) carbamoyl)- 4-(1-methyl- pyrrolidin-2- yl)benzene- CHIRAL-PAK IG, 20*250 mm, 5 um IPA in Hex: DCM = 5:1 (10 mM NH₃- MeOH) 439sulfonimi- damide 409 380c

(R,S) or (S,R) or (S,R) or (R,R)-N- ((1,2,3,5,6,7- hexahydro-s-indacen-4-yl) carbamoyl)- 4-(1-methyl- pyrrolidin-2- yl)benzene- CHIRAL-PAK IG, 20*250 mm, 5 um IPA in Hex: DCM = 5:1 (10 mM NH₃- MeOH) 439sulfonimi- damide 410 380d

(R,S) or (S,R) or (R,S or (S,S)-N- ((1,2,3,5,6,7- hexahydro-s-indacen-4-yl) carbamoyl)- 4-(1-methyl- pyrrolidin-2- yl)benzene- CHIRAL-PAK IG, 20*250 mm, 5 um IPA in Hex: DCM = 5:1 (10 mM NH₃- MeOH) 439sulfonimi- damide 411 384a

(R) or (S)-4- (amino- methyl)-N′- ((1,2,3,5,6,7- hexahydro-s-indacen-4-yl) carbamoyl) benzene- sulfonimi- damide CHIRAL- PAK IG, 2*25cm, 5 um EtOH in Hex (8 mM NH₃- MeOH) 385 412 384b

(S) or (R)-4- (amino- methyl)-N′- ((1,2,3,5,6,7- hexahydro-s-indacen-4-yl) carbamoyl) benzene- sulfonimi- damide CHIRAL- PAK IG, 2*25cm, 5 um EtOH in Hex (8 mM NH₃- MeOH) 385 413 357a

(R) or (S)-5- ((dimethyl- amino) methyl)-N′- ((1,2,3,5,6,7- hexahydro-s-indacen-4-yl) carbamoyl) pyridine-2- sulfonimi- CHIRAL- PAK AD-H,2.0.*25 cm EtOH in Hex (8 mM NH₃- MeOH) 414 damide 414 357b

(S) or (R)-5- ((dimethyl- amino) methyl)-N′- ((1,2,3,5,6,7- hexahydro-s-indacen-4-yl) carbamoyl) pyridine-2- sulfonimi- CHIRAL- PAK AD-H,2.0.*25 cm EtOH in Hex (8 mM NH₃- MeOH) 414 damide 415 354a

(R) or (S)-N′- ((1,2,3,5,6,7- hexahydro-s- indacen-4-yl) carbamoyl)-6-isobutyl- pyridine-3- sulfonimi- damide CHIRAL ART Cellu- lose- SB,2*25 cm, 5 um EtOH in Hex (0.1% DEA) 413 416 354b

(S) or (R)-N′- ((1,2,3,5,6,7- hexahydro-s- indacen-4-yl) carbamoyl)-6-isobutyl- pyridine-3- sulfonimi- damide CHIRAL ART Cellu- lose- SB,2*25 cm, 5 um EtOH in Hex (0.1% DEA) 413 417 387a

(R) or (S)-2- acetyl-N′- ((1,2,3,5,6,7- hexahydro-s- indacen-4-yl)carbamoyl) thiazole-5- sulfonimi- damide CHIRAL ART Cellu- lose- SB,2*25 cm, 5 um IPA in CO₂ 405 418 387b

(S) or (R)-2- acetyl-N′- ((1,2,3,5,6,7- hexahydro-s- indacen-4-yl)carbamoyl) thiazole-5- sulfonimi- damide CHIRAL ART Cellu- lose- SB,2*25 cm, 5 um IPA in CO₂ 405 419 333a

(R) or (S)-N′- ((1,2,3,6,7,8- hexahydro-as- indacen-4-yl) carbamoyl)-2-(2-hydroxy- propan-2-yl) thiazole-5- sulfonimi- damide CHIRAL- PAK IF,5*25 cm, 5 um EtOH in Hex (8 mM NH₃- MeOH) 421 420 333b

(S) or (R)-N′- ((1,2,3,6,7,8- hexahydro-as- indacen-4-yl) carbamoyl)-2-(2-hydroxy- propan-2-yl) thiazole-5- sulfonimi- damide CHIRAL- PAK IF,5*25 cm, 5 um EtOH in Hex (8 mM NH₃- MeOH) 421 421 375a

(R) or (S)-N′- ((1,2,3,5,6,7- hexahydro-s- indacen-4-yl- 3,3,5,5-d₄)carbamoyl)- 2-(2-hydroxy- propan-2-yl) thiazole-5- sulfonimi- damideCHIRAL- PAK IF, 2*25 cm, 5 um MeOH (2 mM NH₃- MeOH) in CO₂ 425 422 375b

(S) or (R)-N′- ((1,2,3,5,6,7- hexahydro-s- indacen-4-yl- 3,3,5,5-d₄)carbamoyl)- 2-(2-hydroxy- propan-2-yl) thiazole-5- sulfonimi- damideCHIRAL- PAK IF, 2*25 cm, 5 um MeOH (2 mM NH₃- MeOH) in CO₂ 425 423 376a

(R) or (S)-N′- ((1,2,3,5,6,7- hexahydro-s- indacen-4-yl- 1,1,7,7-d₄)carbamoyl)- 2-(2-hydroxy- propan-2-yl) thiazole-5- sulfonimi- damideCHIRAL- PAK ID, 2*25 cm (5 um) MeOH (2 mM NH₃- MeOH) in CO₂ 425 424 376b

(S) or (R)-N′- ((1,2,3,5,6,7- hexahydro-s- indacen-4-yl- 1,1,7,7-d₄)carbamoyl)- 2-(2-hydroxy- propan-2-yl) thiazole-5- sulfonimi- damideCHIRAL- PAK ID, 2*25 cm (5 um) MeOH (2 mM NH₃- MeOH) in CO₂ 425 ^(#)Theamount of NH₃ in this chiral chromatographic solvent and similarsolvents were adjusted by adding 2M NH₃ in methanol to the desired NH₃concentration. In this case, the resulting concentration of NH₃ inmethanol is 8 mM.

Example 425 (Compound 318)1-{Amino[5-(2-hydroxypropan-2-yl)-1,3-thiazol-2-yl]oxo-λ⁶-sulfanylidene}-3-(8-bromo-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea

Step 1: 4-Bromo-1,2,3,5,6,7-hexahydro-8-isocyanato-s-indacene

To a solution of 8-bromo-1,2,3,5,6,7-hexahydros-indacen-4-amine (1.5 g,5.94 mmol) in anhydrous THF (50 mL) was added triethylamine (1.07 mL,7.73 mmol) and triphosgene (882 mg, 2.97 mmol) at room temperature. Theresulting mixture was then stirred at 60° C. for 4 h. Reaction mixturewas then brought to room temperature and used directly in the next step.

Step 2:1-{Amino[5-(2-hydroxypropan-2-yl)-1,3-thiazol-2-yl]oxo-λ⁶-sulfanylidene}-3-(8-bromo-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea

To a solution ofN-(tert-butyldimethylsilyl)-5-(2-hydroxypropan-2-yl)-1,3-thiazole-2-sulfonoimidamide(400 mg, 1.2 mmol) in anhydrous THF (10 mL) was added NaH (60% wt. oildispersioin, 96 mg, 2.4 mmol) at room temperature. After 5 min, asolution of 4-bromo-1,2,3,5,6,7-hexahydro-8-isocyanato-s-indacene (2 mL,2 mmol, from Step 1) was added drop wise. The resulting mixture wasstirred at room temperature for 20 min before quenching carefully with 4M HCl solution in dioxane (3 mL). Saturated aqueous ammonium chloridewas added and the mixture was extracted with dichloromethane (15 mL×3).The combined organic layers were washed with brine, dried over MgSO₄,filtered, and concentrated in vacuo. The crude product was purified byprep-HPLC to obtain the titled compound (280 mg, 47%). LCMS:[M+H]⁺=499.3.

Example 426 (Compound 313)1-{Amino[5-(2-hydroxypropan-2-yl)-1,3-thiazol-2-yl]oxo-λ⁶-sulfanylidene}-3-[7-(3,4-dimethylphenyl)-2,3-dihydro-1H-inden-4-yl]urea

Step 1: N-(2,3-dihydro-1H-inden-4-yl)acetamide

To a solution of 2,3-dihydro-1H-inden-4-amine (3.4 g, 26 mmol) inethanol (45 mL) was added a solution of acetic anhydride (4.9 mL, 52mmol) in ethanol (15 mL) dropwise at 0° C. The resulting mixture wasgradually warmed up to RT and stirred for 15 h. Solvent was removedunder reduced pressure and the residue was triturated with diethyl etherto afford titled compound as off white solid (3 g, 66%). LCMS[M+H]⁺=176.3.

Step 2: N-(4-bromo-2,3-dihydro-1H-inden-7-yl)acetamide

Into a 250-mL round-bottom flask was addedN-(2,3-dihydro-1H-inden-4-yl)acetamide (3 g, 17.1 mmol) and acetic acid(45 mL). The resulting solution was cooled to 0° C. and then a solutionof bromine (5.4 g, 34.2 mmol) in acetic acid (12 mL) was added dropwisewith stirring over 10 min. The cooling bath was removed and the reactionmixture was stirred at RT for 1 h. Water was added and the resultingprecipitates of product were collected by filtration and dried undervacuum to afford titled compound as off white solid (3.9 g, 90%). LCMS[M+H]⁺=254.4.

Step 3: N-(2,3-dihydro-4-(3,4-dimethylphenyl)-1H-inden-7-yl)acetamide

A mixture of N-(4-bromo-2,3-dihydro-1H-inden-7-yl)acetamide (1 g, 3.9mmol), 3,4-dimethylphenylboronic acid (700 mg, 4.68 mmol),Pd(dppf)Cl₂.DCM (160 mg, 0.19 mmol), sodium carbonate (900 mg, 8.58 mmolas 2 M aqueous solution) in dioxane (12 mL) was stirred at 100° C. in anoil bath for 72 h. The reaction mixture was brought to RT, water (20 mL)was added and extracted with EtOAc (15 mL×3). The combined organiclayers were washed with brine, dried over MgSO₄, filtered, andconcentrated in vacuo. The crude product was purified by silica gelflash chromatography using 0-30% gradient of EtOAc in hexanes to affordtitled compound (880 mg, 81%). LCMS [M+H]⁺=280.6.

Step 4: 2,3-Dihydro-7-(3,4-dimethylphenyl)-1H-inden-4-amine

A solution ofN-(2,3-dihydro-4-(3,4-dimethylphenyl)-1H-inden-7-yl)acetamide (880 mg,3.15 mmol) in 6 N HCl (20 mL) was stirred at 100° C. for 40 h. Afterconsumption of the starting material, the reaction mixture was cooled to0° C. and adjusted to pH=8 with 10 M aqueous sodium hydroxide solution.The precipitates formed were collected, washed with water and driedunder vacuum to afford the titled compound (81 mg, 67%) as tan coloredpowder. LCMS [M+H]⁺=238.3.

Step 5:1-{Amino[5-(2-hydroxypropan-2-yl)-1,3-thiazol-2-yl]oxo-λ⁶-sulfanylidene}-3-[7-(3,4-dimethylphenyl)-2,3-dihydro-1H-inden-4-yl]urea

To a solution of N-(tert-butyldimethylsilyl)-5-(2-hydroxypropan-2-yl)-1,3-thiazole-2-sulfonoimidamide (42 mg,0.13 mmol) in DMF (1 mL) was added Et₃N (35 uL, 0.25 mmol) and theresulting mixture was stirred at room temperature for 10 min, followedby the addition of CDI (41 mg, 0.25 mmol). The reaction mixture wasfurther stirred at RT for 1 h, and then2,3-dihydro-7-(3,4-dimethylphenyl)-1H-inden-4-amine (30 mg, 0.13 mmol)was added. The resulting reaction mixture was stirred overnight at roomtemperature. The presence of desired product was then confirmed byLC-MS. The reaction mixture was quenched with 4 M HCl in dioxane (1 mL)and stirred for 30 min to de-protect the TBS group which indicated theformation of desired product on LCMS. The crude product was purified bypreparative HPLC to provide titled compound (16.4 mg, 27%). LCMS[M+H]⁺=485.49.

Example 427 (Compound 314)1-{Amino[5-(2-hydroxypropan-2-yl)-1,3-thiazol-2-yl]oxo-λ⁶-sulfanylidene}-3-[8-(3,4-dimethylphenyl)-1,2,3,5,6,7-hexahydro-s-indacen-4-yl]urea

Step 1: 1,2,3,5,6,7-Hexahydro-8-(3,4-dimethylphenyl)-s-indacen-4-amine

8-Bromo-1,2,3,5,6,7-hexahydro-s-indacen-4-amine (105 mg, 0.42 mmol),3,4-dimethylphenyl-boronic acid (187 mg, 1.25 mmol), Pd(dppf)C₁₂ (30.4mg, 0.04 mmol) and dioxane (1.5 mL) were added to a reaction vial.Cesium carbonate (1.24 mL, 1 M in H₂O) was then added and the reactionmixture was stirred at 80° C. for 16 h. Reaction mixture was brought toRT and filtered through a small bed of Celite and rinsed with dioxane (5mL). Water (5 mL) was added to the filtrates and extracted with diethylether (5 mL×3). The combined organic layers were washed with brine,dried over anhydrous MgSO₄, filtered, and concentrated in vacuo toprovide titled compound which was used in the next step without anypurification. LCMS [M+H]⁺=278.4.

Step 2:1-{Amino[5-(2-hydroxypropan-2-yl)-1,3-thiazol-2-yl]oxo-λ⁶-sulfanylidene}-3-[8-(3,4-dimethylphenyl)-1,2,3,5,6,7-hexahydro-s-indacen-4-yl]urea

The title product was obtained using similar procedure as in Step 5Example 426. LCMS: [M+H]⁺=525.42.

Example 428 (Compound 309)3-[Amino(dimethyl-1,3-thiazol-5-yl)oxo-λ⁶-sulfanylidene]-1-[4-fluoro-2,6-bis(propan-2-yl)phenyl]urea

Step 1:N-(tert-butyldimethylsilyl)-2,4-dimethyl-1,3-thiazole-5-sulfonamide

Dimethyl-1,3-thiazole-5-sulfonamide (41.4 mg, 0.22 mmol) was dissolvedin anhydrous CH₂C₁₂ (2 mL). Triethylamine (0.090 mL, 0.65 mmol) andTBSCl (38 mg, 0.25 mol) were added and the resulting mixture was stirredat 50° C. for 18 h. Reaction mixture was brought to RT and used directlyin the next step. LCMS: [M+H]⁺=307.2.

Step 2:N-(tert-butyldimethylsilyl)-2,4-dimethyl-1,3-thiazole-5-sulfonoimidamide

Polymer bound dichlorotriphenylphosphorane reaction mixture (describedfor Reagent 2) was cooled in an ice/water bath under nitrogen.Triethylamine (0.1 mL, 0.72 mmol, 2.25 equiv.) was added slowly viasyringe. Resulting mixture was stirred at 0° C. for 10 min and then thereaction mixture from Step 1 above was added dropwise via syringe. Thisreaction mixture was further stirred at 0° C. for 30 min and then asteady stream of anhydrous ammonia was bubbled into the reaction mixturefor 3 min. Reaction vial was screw capped and stirred in ice/water bathfor 2 h. Reaction mixture was warmed up to room temperature, carefullyopened and filtered to remove resin. The cloudy filtrate was centrifugedto remove any solids. Supernatant was concentrated in vacuo and driedunder high vacuum for 1 h and used directly in the next step. LCMS:[M+H]⁺=306.8.

Step 3:3-{[(Tert-butyldimethylsilyl)amino](dimethyl-1,3-thiazol-5-yl)oxo-λ⁶-sulfanylidene}-1-[4-fluoro-2,6-bis(propan-2-yl)phenyl]urea

To the crude reaction mixture from Step 2 was added anhydrous THF (1.5mL) and the resulting mixture was stirred in an ice/water bath for 5min. NaH (17 mg, 0.44 mmol) was added and after 2 min of stirring asolution of isocyanate (0.165 mmol) in THF (3 ml) was added dropwise at0° C. The resulting mixture was brought to RT and stirred for 15 min togive a mixture of crude products. LCMS: [M+H]⁺=527.5; for de-protectedproduct, [M+H]⁺=413.5.

Step 4:3-[amino(dimethyl-1,3-thiazol-5-yl)oxo-λ⁶-sulfanylidene]-1-[4-fluoro-2,6-bis(propan-2-yl)phenyl]urea

To the reaction from Step 3 was carefully added 4N HCl in dioxane (0.3mL) and the resulting mixture was stirred at RT for 30 min or till thecompletion of reaction as determined by the LCMS analysis([M+H]⁺=413.5). Reaction mix was then concentrated in vacuo. DMSO (0.8mL) was added to the residue and purified by prep-HPLC to afford titledcompound (10 mg).

Examples in the following table were prepared using similar proceduresdescribed in Example 428.

TABLE 29 Example Final LCMS: # Target # IUPAC Name Structure [M + H]⁺428 309 3-[amino(dimethy1-1,3- thiazol-5-yl)oxo-λ⁶-sulfanylidene]-1-[4-fluoro- 2,6-bis(propan-2- yl)phenyl]urea

413.16 430 310 3-[amino({1-methy1-1H- pyrazolo[3,4-b]pyridin-5-yl})oxo-λ⁶-sulfanylidene]- 1-[4-fluoro-2,6-bis(propan- 2-yl)phenyl]urea

433.27 431 306 1-{amino[5- (dimethylamino)naphthalen- 1-yl]oxo-λ⁶sulfanylidene}-3-[4-fluoro- 2,6-bis(propan-2- yl)phenyl]urea

471.70

The following protocol is suitable for testing the activity of thecompounds disclosed herein.

Procedure 1: IL-1β Production in PMA-Differentiated THP-1 CellsStimulated with Gramicidin.

THP-1 cells were purchased from the American Type Culture Collection andsub-cultured according to instructions from the supplier. Cells werecultured in complete RPMI 1640 (containing 10% heat inactivated FBS,penicillin (100 units/ml) and streptomycin (100 μg/ml)), and maintainedin log phase prior to experimental setup. Prior to the experiment,compounds were dissolved in dimethyl sulfoxide (DMSO) to generate a 30mM stock. The compound stock was first pre-diluted in DMSO to 3, 0.34,0.042 and 0.0083 mM intermediate concentrations and subsequently spottedusing Echo550 liquid handler into an empty 384-well assay plate toachieve desired final concentration (e.g. 100, 33, 11, 3.7, 1.2, 0.41,0.14, 0.046, 0.015, 0.0051, 0.0017 μM). DMSO was backfilled in the plateto achieve a final DMSO assay concentration of 0.37%. The plate was thensealed and stored at room temperature until required.

THP-1 cells were treated with PMA (Phorbol 12-myristate 13-acetate) (20ng/ml) for 16-18 hours. On the day of the experiment the media wasremoved and adherent cells were detached with trypsin for 5 minutes.Cells were then harvested, washed with complete RPMI 1640, spun down,and resuspended in RPMI 1640 (containing 2% heat inactivated FBS,penicillin (100 units/ml) and streptomycin (100 μg/ml). The cells wereplated in the 384-well assay plate containing the spotted compounds at adensity of 50,000 cells/well (final assay volume 50 μl). Cells wereincubated with compounds for 1 hour and then stimulated with gramicidin(5 μM) (Enzo) for 2 hours. Plates were then centrifuged at 340 g for 5min. Cell free supernatant (40 μL) was collected using a 96-channelPlateMaster (Gilson) and the production of IL-1(3 was evaluated by HTRF(cisbio). The plates were incubated for 18 h at 4° C. and read using thepreset HTRF program (donor emission at 620 nm, acceptor emission at 668nm) of the SpectraMax i3× spectrophotometer (Molecular Devices, softwareSoftMax 6). A vehicle only control and a dose titration of CRID3(100-0.0017 μM) were run concurrently with each experiment. Data wasnormalized to vehicle-treated samples (equivalent to 0% inhibition) andCRID3 at 100 μM (equivalent to 100% inhibition). Compounds exhibited aconcentration-dependent inhibition of IL-1(3 production inPMA-differentiated THP-1 cells.

Procedure 2: IL-1β Production in PMA-Differentiated THP-1 CellsStimulated with Gramicidin.

THP-1 cells were purchased from the American Type Culture Collection andsub-cultured according to instructions from the supplier. Prior toexperiments, cells were cultured in complete RPMI 1640 (containing 10%heat inactivated FBS, penicillin (100 units/ml) and streptomycin (100μg/ml)), and maintained in log phase prior to experimental setup. Priorto the experiment THP-1 were treated with PMA (Phorbol 12-myristate13-acetate) (20 ng/ml) for 16-18 hours. Compounds were dissolved indimethyl sulfoxide (DMSO) to generate a 30 mM stock. On the day of theexperiment the media was removed and adherent cells were detached withtrypsin for 5 minutes. Cells were then harvested, washed with completeRPMI 1640, spun down, resuspended in RPMI 1640 (containing 2% heatinactivated FBS, penicillin (100 units/ml) and streptomycin (100 μg/ml).The cells were plated in a 384-well plate at a density of 50,000cells/well (final assay volume 50 μl). Compounds were first dissolved inassay medium to obtain a 5× top concentration of 500 μM. 10 stepdilutions (1:3) were then undertaken in assay medium containing 1.67%DMSO. 5× compound solutions were added to the culture medium to achievedesired final concentration (e.g. 100, 33, 11, 3.7, 1.2, 0.41, 0.14,0.046, 0.015, 0.0051, 0.0017 μM). Final DMSO concentration was at 0.37%.Cells were incubated with compounds for 1 hour and then stimulated withgramicidin (5 μM) (Enzo) for 2 hours. Plates were then centrifuged at340 g for 5 min. Cell free supernatant (40 μL) was collected using a96-channel PlateMaster (Gilson) and the production of IL-1β wasevaluated by HTRF (cisbio). A vehicle only control and a dose titrationof CRID3 (100-0.0017 μM) were run concurrently with each experiment.Data was normalized to vehicle-treated samples (equivalent to 0%inhibition) and CRID3 at 100 μM (equivalent to 100% inhibition).Compounds exhibited a concentration-dependent inhibition of IL-1βproduction in PMA-differentiated THP-1 cells.

Procedure 3 1. Experimental Procedure

1.1 Cell Culture

-   -   1) Culture THP-1 cells in the complete RPMI-1640 medium with 10%        FBS at 37° C., 5% CO₂.    -   2) Passage the cells every 3 days by inoculating 3×10⁵ cells per        ml.

1.2 Compound Preparation

-   -   Prepare the 3-fold serial dilution of the compounds with DMSO in        a 384-well LDV Microplate using TECAN EVO system to generate the        compound source plate with 10 concentrations. Top concentration        is 30 mM. FIG. 3 depicts the layout of the microplate.

1.3 Cell Preparation

-   -   1) Centrifuge THP-1 cells at 350 g for 5 min.    -   2) Re-suspend cells with complete RMPI-1640 medium, and count        cells.    -   3) Seed cells in T225 flask, about 2.5×10⁷ per flask, treat        cells with 20 ng/ml PMA (final DMSO concentration<1%).    -   4) Incubate overnight.

1.4 THP-1 Stimulation

-   -   1) Wash adherent THP-1 cells with PBS, and detach cells with 4        ml trypsin for T225 flask.    -   2) Centrifuge cells at 350 g for 5 min, re-suspend cells with        RPMI-1640 containing 2% FBS and count cells with trypan blue.    -   3) Transfer 50 nl/well the serial dilution of test compound to        384-well plate by Echo; For the high control and first point of        CRID3 (MCC950), transfer 165 nl, then backfill to make the DMSO        concentration is consistent in all wells, the plate layout is as        below.    -   4) Seed 50 k cells in 40 ul RPMI-1640 with 2% FBS per well in        384-well plate.    -   5) Incubate for 1 h at 37° C., 5% CO₂.    -   6) Prepare 5× gramicidin, add 10 μl per well, the final        concentration is 5 μM, incubate for 2 hrs at 37° C., 5% CO₂.    -   7) Centrifuge at 350 g for 1 min.    -   8) Pipet 16 μl supernatant by apricot, and transfer into white        384 proxiplate. FIG. 3 depicts the layout of the plates: HC: 100        μM CRID3 (MCC950)+5 μM gramicidin LC: 5 μM Gramicidin.

1.5 IL-1β Detection

-   -   1) Homogenize the 5× diluent #5 with a vortex and add 1 volume        of stock solution in 4 volumes of distilled water.    -   2) Thaw 20× stock solution of anti-IL1β-Cryptate-antibody and        anti-IL1β XL-antibody. Dilute these two antibodies to 1× with        detection buffer #3.    -   3) Pre-mix the two ready-to-use antibody solutions just prior to        use. 4) Dispense 4 ul of pre-mixed Anti-IL1β antibodies working        solution into all wells.    -   5) Seal the plate and incubate overnight at 4° C.    -   6) Read the cell plate using EnVison and plot Readout vs. the        test compound concentration to calculate the IC₅₀.

2. Data Analysis

-   -   1. IC₅₀ of compounds can be calculated using the following        formulas

% inhibition=100−100×[HC_(ave)−Readout/(HC_(ave)−LC_(ave))]  Formula forIC₅₀

-   -   2. Fit the normalized data in a dose-response manner using        XLfit, and calculate the compound concentration.        Table 30 shows the biological activity of compounds in hTHP-1        assay containing 2% fetal bovine serum: <0.008 μM=“++++++”;        ≥0.008 and <0.04 μM=“+++++”; ≥0.04 and <0.2 μM=“++++”; ≥0.2 and        <1 μM=“+++”; ≥1 and <5 μM=“++”; ≥5 and <30 μM=“+”.

TABLE 30 Average IC₅₀ of compounds in hTHP-1 assay Example # CompoundNumber hTHP-1 IC₅₀ 1 181 +++++ 2  181a +++++ 3  181b +++ 4  101′ ++++ 5101 or 102 +++ 6 102 or 101 +++++ 7 194 +++ 8 270 + 9 204 >30 μM 10 180++++ 11 190 + 12 182 ++++ 13 191 ++++ 14 177 +++++ 15 185 ++++ 16 186++++ 17 187 +++++ 18 188 +++ 19 192 ++ 20 189 ++++ 21 178 ++++ 22 193 ++23 170 ++++ 24 168 ++ 25 171 ++++ 26 122 ++++ 27 120 +++ 28 125 ++++ 29129 + 30 213 +++++ 31 207 ++++ 32 195 +++++ 33 179 ++++ 34 105 ++ 35 121+++ 36 145 ++ 37 131 ++ 38 132 ++++ 39 144 +++ 40 149 ++++ 41 152 ++++42 150 + 43 167 ++++ 44 106 +++++ 45 107 ++++++ 46 110 ++ 47 151 +++ 48154 ++++ 49 148 +++ 50 153 ++ 51 109 ++ 52 135 +++ 53 134 +++++ 54 130++ 55 212 +++ 56 205 +++ 57 143 +++ 58 206 ++ 59 108 +++++ 60 202 ++ 61208 +++++ 62 197 ++++ 63 196 ++ 64 124 ++++ 65 173 ++++ 66 172 + 67 174+++ 68 158 ++ 69 220 ++ 70 157 ++ 71 161 ++ 72 159 +++ 73 165 ++ 74 183+++++ 75 176 +++++ 76 136 +++++ 77 209 ++++ 78 203 >30 μM 79 180b or180a +++++ 80 180a or 180b +++ 81  179b +++++ 82  179a +++ 83 190a or190b ++ 84 190b or 190a >30 μM 85 182a or 182b +++++ 86 182b or 182a +++87 191b or 191a ++++ 88 191a or 191b ++ 89 177b or 177a +++++ 90 177a or177b +++ 91 185b or 185a ++++ 92 185a or 185b ++ 93 186a or 186b ++++ 94186b or 186a ++ 95 187a or 187b ++++++ 96 187b or 187a +++ 97 188b or188a ++++ 98 188a or 188b + 99 192b or 192a +++ 100 192a or 192b + 101189b or 189a ++++ 102 189a or 189b ++ 103 178b or 178a ++++ 104 178a or178b ++ 105 193b or 193a +++ 106 193a or 193b + 107 170b or 170a + 108170a or 170b ++++ 109 168b or 168a +++ 110 168a or 168b >30 μM 111 171bor 171a ++++ 112 171a or 171b + 113 122b or 122a +++++ 114 122a or 122b++ 115 120b or 120a ++ 116 120a or 120b ++++ 117 125b or 125a ++++ 118125a or 125b ++ 119 129b or 129a + 120 129a or 129b >30 μM 121 112b or112a +++++ 122 112a or 112b +++ 123  207c ++++ 124  207aa ++ 125  207b++++ 126 195a or 195e ++ 127 195e or 195a ++++ 128 105b or 105a +++ 129105a or 105b + 130 121b or 121a ++++ 131 121a or 121b ++ 132 145b or145a ++ 133 145a or 145b >30 μM 134 131b or 131a >30 μM 135 131a or 131b++ 136 225b or 225a ++ 137 225a or 225b ++++ 138 144b or 144a ++ 139144a or 144b ++++ 140 149b or 149a +++++ 141 149a or 149b ++ 142 152b or152a ++++ 143 152a or 152b + 144 151b′ or 151a′ >30 μM 145 151a′ or151b′ + 146 167b or 167a ++ 147 167a or 167b +++ 148 107b or 107a ++++++149 107a or 107b +++ 150 110b or 110a + 151 110a or 110b +++ 152 151b or151a ++++ 153 151a or 151b ++ 154 154b or 154a ++++ 155 154a or 154b ++156 148b or 148a +++ 157 148a or 148b + 158 153b or 153a ++ 159 153a or153b + 160 109b or 109a +++ 161 109a or 109b + 162 135b or 135a +++ 163135a or 135b + 164 134b or 134a +++++ 165 134a or 134b ++ 166 130b or130a +++ 167 130a or 130b >11.2150 168 212b or 212a +++ 169 212a or 212b >5.5915 170 205b or 205a ++ 171 205a or 205b +++ 172 143b or 143a +++173 143a or 143b ++ 174 206b or 206a +++ 175 206a or 206b ++ 176 108b or108a +++++ 177 108a or 108b ++ 178 202b or 202a + 179 202a or 202b ++180 116b or 116a ++ 181 116a or 116b + 182 173a or 173b +++++ 183 173bor 173a +++ 184 174b or 174a +++ 185 174a or 174b + 186 223b or 223a++++ 187 223a or 223b + 188 158b or 158a ++ 189 158a or 158b >30 μM 190220b or 220a +++ 191 220a or 220b + 192 157a or 157b +++ 193 157b or157a >30 μM 194 161b or 161a ++ 195 161a or 161b + 196 165b or 165a +197 165a or 165b >30 μM 198 172b or 172a + 199 172a or 172b >30 μM 200106a or 106b +++++ 201 106b or 106a +++ 202 136b or 136a ++ 203 136a or136b ++++++ 204 183a or 183b +++ 205 183b or 183a +++++ 206 176b or 176a+++++ 207 176a or 176b +++ 208 221 + 209 219 >30 μM 210 217 >30 μM 211216 + 212 215 >30 μM 213 218 >30 μM 214 214 >30 μM 215 211 + 216 210 >30μM 217 201 + 218 200 ++ 219 199 >30 μM 220 198 + 221 141 ++++ 222 140+++ 223 321 +++++ 224 321b or 321a +++++ 225 321a or 321b ++ 226 329+++++ 227 375 ++++ 228 376 ++++ 229 307 ++ 230 323 ++ 231 338 ++ 232 341++ 233 342 ++ 234 345 ++ 235 346 ++ 236 347 ++ 237 348 ++ 238 403 ++ 239402 ++ 240 350 ++ 241 322 ++ 242 351 ++ 243 358 ++ 244 401 + 245 404 +246 331 + 247 339 + 248 405 + 249 406 >30 μM 250 324 + 251 407 ++ 252410 >30 μM 253 408 254 308 ++ 255 311 + 256 312 >30 μM 257 327 ++++ 258326 ++++ 259 139 +++ 260 137 +++ 261 409 ++ 262 303 +++++ 263 325 +++++264 138 ++ 265 332 ++++ 266 334 ++++ 267 335 ++++ 268 337 ++ 269 113+++++ 270 343 ++ 271 349 ++ 272 344 +++ 273 359 + 274 352 +++ 275 354 ++276 355 +++ 277 356 >30 μM 278 357 +++ 279 340 +++++ 280 377 +++ 281 378+++++ 282 379 +++ 283 380 +++ 284 353 + 285 333 ++++ 287 382 ++ 288 383++ 289 315 ++++ 290 316 ++ 291 317 ++++ 292 319 ++++ 293 320 +++ 294 336++++ 295 330 ++++ 296  364a ++++++ 297  364b +++ 298  365a ++++ 299 365b ++ 300  308a +++ 301  308b + 302 195ba or 195bb +++ 303 195bb or195ba +++++ 304  207a or 207bb ++++ 305 207bb or 207a  +++++ 306  366a++++++ 307  366b ++++ 308  139a ++ 309  139b ++++ 310  367a +++++ 311 367b +++ 312  409b ++ 313  409a ++ 314  369a +++ 315  369b + 316  159a+++ 317  159ab ++ 318  159ba +++ 319  137a ++ 320  137b ++++ 321  317ab++ 322  317aa +++ 323  317bb ++++ 324  317ba +++++ 325  316a >28.4352326  316b + 327  373a >30 μM 328  373b ++ 329  374a >30 μM 330  374b >30μM 331  319ab + 332  319aa +++ 333  319bb ++ 334  319ba +++++ 335  320a++ 336  320b +++ 337  323ab ++ 338  323bb ++ 339  323aa ++ 340  323ba ++341  303a ++++++ 342  303b +++ 343  315a ++++ 344  315b ++ 345  138a +++346  138b + 347  328a +++++ 348  328b ++ 349  326b ++ 350  326a ++++ 351 318a +++ 352  318b ++++ 353  325a ++ 354  325b +++++ 355  329a ++++++356  329b +++ 357  404b + 358  404a >30 μM 359  332a +++++ 360  332b +++361  335a ++++ 362  335b ++ 363  336a ++ 364  336b ++++ 365  337a >30 μM366  337b ++ 367  371a >30 μM 368  371b ++ 369  372a >30 μM 370  372b+++ 371  334a + 372  334b ++++ 373  339a + 374  339b +++++ 375  334ab +376  334aa + 377  334bb ++++ 378  334ba +++ 379  338a ++ 380  338b >30μM 381  340a +++++ 382  340b ++ 383  361b >30 μM 384  361a >30 μM 385 113a +++++ 386  113b +++ 387  330a ++ 388  330b ++++ 389  341a >30 μM390  341b ++ 391  360ba +++ 392  360bb +++ 393  363b +++++ 394  363a +++395  343a ++ 396  343b >30 μM 397  359a ++ 398  359b >30 μM 399  352a+++ 400  352b + 401  383a >30 μM 402  383b ++ 403  382a +++ 404  382b +405  379a 406  379b >30 μM 407  380a + 408  380b ++ 409  380c +++ 410 380d ++++ 411  384a ++ 412  384b >30 μM 413  357a +++ 414  357b + 415 354a >30 μM 416  354b +++ 417  387a ++ 418  387b ++++ 419  333a ++++420  333b ++ 421  375a +++++ 422  375b 423  376a +++++ 424  376b 425 318+++ 426 313 + 427 314 + 428 309 + 430 310 + 431 306 +

A number of embodiments of the invention have been described.Nevertheless, it will be understood that various modifications may bemade without departing from the spirit and scope of the invention.Accordingly, other embodiments are within the scope of the followingclaims.

1.-122. (canceled)
 123. A compound of Formula AA

wherein m=0, 1, or 2; n=0, 1, or 2; o=1 or 2; p=0, 1, or 3, wherein A isa 5- to 10-membered monocyclic or bicyclic heteroaryl or a C₆-C₁₀monocyclic or bicyclic aryl; B is a 5-membered heteroaryl, a 7-10membered monocyclic or bicyclic heteroaryl, or a C₆-C₁₀ monocyclic orbicyclic aryl; wherein at least one R⁶ is ortho to the bond connectingthe B ring to the NH(CO) group of Formula AA; R¹ and R² are eachindependently selected from C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy,C₁-C₆ haloalkoxy, halo, CN, NO₂, COC₁-C₆ alkyl, CO—C₆-C₁₀ aryl; CO (5-to 10-membered heteroaryl); CO₂C₁-C₆ alkyl, CO₂C₃-C₈ cycloalkyl,OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO (5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C₆-C₁₀ aryl, 5- to 10-memberedheteroaryl, NH₂, NHC₁-C₆ alkyl, N(C₁-C₆ alkyl)₂, NHCOC₁-C₆ alkyl,NHCOC₆-C₁₀ aryl, NHCO (5- to 10-membered heteroaryl), NHCO (3- to7-membered heterocycloalkyl), NHCOC₂-C₆ alkynyl, NHCOOCC₁-C₆ alkyl,NH—(C═NR¹³)NR¹¹R¹², CONR⁸R⁹, SF₅, SC₁-C₆ alkyl, S(O₂)C₁-C₆ alkyl,S(O)C₁-C₆ alkyl, S(O₂)NR¹¹R¹², C₃-C₇ cycloalkyl and 3- to 7-memberedheterocycloalkyl, wherein the C₃-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₇cycloalkyl and 3- to 7-membered heterocycloalkyl is optionallysubstituted with one or more substituents each independently selectedfrom hydroxy, halo, CN, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰,COOC₁-C₆ alkyl CONR⁸R⁹, 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl,5- to 10-membered heteroaryl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO (5- to10-membered heteroaryl), OCO (3- to 7-membered heterocycloalkyl),NHCOC₁-C₆ alkyl, NHCOC₆-C₁₀ aryl, NHCO (5- to 10-membered heteroaryl),NHCO (3- to 7-membered heterocycloalkyl), and NHCOC₂-C₆ alkynyl; whereineach C₁-C₆ alkyl substituent and each C₁-C₆ alkoxy substituent of the R¹or R² C₃-C₇ cycloalkyl or of the R¹ or R² 3- to 7-memberedheterocycloalkyl is further optionally independently substituted withone to three hydroxy, halo, NR⁸R⁹, or oxo; wherein the 3- to 7-memberedheterocycloalkyl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, NHCOC₆-C₁₀aryl, NHCO (5- to 10-membered heteroaryl) and NHCO (3- to 7-memberedheterocycloalkyl) are optionally substituted with one or moresubstituents independently selected from halo, C₁-C₆ alkyl, and OC₁-C₆alkyl; or at least one pair of R¹ and R² on adjacent atoms, takentogether with the atoms connecting them, independently form at least oneC₄-C₈ carbocyclic ring or at least one 5- to 8-membered heterocyclicring containing 1 or 2 heteroatoms independently selected from O, N, andS, wherein the carbocyclic ring or heterocyclic ring is optionallyindependently substituted with one or more substituents independentlyselected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹,═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹ wherein the C₁-C₆ alkyland C₁-C₆ alkoxy are optionally substituted with hydroxy, halo, oxo,NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹; R⁶ and R⁷ areeach independently selected from C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆alkoxy, C₁-C₆ haloalkoxy, halo, CN, NO₂, COC₁-C₆ alkyl, CO₂C₁-C₆ alkyl,CO₂C₃-C₈ cycloalkyl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO (5- to10-membered heteroaryl), OCO (3- to 7-membered heterocycloalkyl), C₆-C₁₀aryl, 5- to 10-membered heteroaryl, NH₂, NHC₁-C₆ alkyl, N(C₁-C₆ alkyl)₂,CONR⁸R⁹, SF₅, S(O₂)C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl and 3- to 10-memberedheterocycloalkyl, and a C₂-C₆ alkenyl, wherein R⁶ and R⁷ are eachoptionally substituted with one or more substituents independentlyselected from hydroxy, halo, CN, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹,═NR¹⁰, COOC₁-C₆ alkyl, CONR⁸R⁹, 3- to 7-membered heterocycloalkyl,C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀aryl, OCO (5- to 10-membered heteroaryl), OCO (3- to 7-memberedheterocycloalkyl), NHCOC₁-C₆ alkyl, NHCOC₆-C₁₀ aryl, NHCO (5- to10-membered heteroaryl), NHCO (3- to 7-membered heterocycloalkyl),NHCOC₂-C₆ alkynyl, C₆-C₁₀ aryloxy, and S(O₂)C₁-C₆ alkyl; and wherein theC₁-C₆ alkyl or C₁-C₆ alkoxy that R⁶ or R⁷ is substituted with isoptionally substituted with one or more hydroxyl, C₆-C₁₀ aryl or NR⁸R⁹,or wherein R⁶ or R⁷ is optionally fused to a five- to -seven-memberedcarbocyclic ring or heterocyclic ring containing one or two heteroatomsindependently selected from oxygen, sulfur and nitrogen; wherein the 3-to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to 10-memberedheteroaryl, NHCOC₆-C₁₀ aryl, NHCO (5- to 10-membered heteroaryl) andNHCO (3- to 7-membered heterocycloalkyl) are optionally substituted withone or more substituents independently selected from halo, C₁-C₆ alkyl,and OC₁-C₆ alkyl; or at least one pair of R⁶ and R⁷ on adjacent atoms,taken together with the atoms connecting them, independently form atleast one C₄-C₈ carbocyclic ring or at least one 5- to 8-memberedheterocyclic ring containing 1 or 2 heteroatoms independently selectedfrom O, N, and S, wherein the carbocyclic ring or heterocyclic ring isoptionally independently substituted with one or more substituentsindependently selected from hydroxy, hydroxymethyl, halo, oxo, C₁-C₆alkyl, C₁-C₆ alkoxy, NR⁸R⁹, CH₂NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀aryl, and CONR⁸R⁹; each of R⁴ and R⁵ is independently selected fromhydrogen and C₁-C₆ alkyl; R¹⁰ is C₁-C₆ alkyl; each of R⁸ and R⁹ at eachoccurrence is independently selected from hydrogen, C₁-C₆ alkyl,(C═NR¹³)NR¹¹R¹², S(O₂)C₁-C₆ alkyl, S(O₂)NR¹¹R¹², COR¹³, CO₂R¹³ andCONR¹¹R¹²; wherein the C₁-C₆ alkyl is optionally substituted with one ormore hydroxy, halo, C₁-C₆ alkoxy, C₆-C₁₀ aryl, 5- to 10-memberedheteroaryl, C₃-C₇ cycloalkyl or 3- to 7-membered heterocycloalkyl; or R⁸and R⁹ taken together with the nitrogen they are attached to form a 3-to 7-membered ring optionally containing one or more heteroatoms inaddition to the nitrogen they are attached to; R¹³ is C₁-C₆ alkyl,C₆-C₁₀ aryl, or 5- to 10-membered heteroaryl; each of R¹¹ and R¹² ateach occurrence is independently selected from hydrogen and C₁-C₆ alkyl;R³ is selected from hydrogen, cyano, hydroxy, C₁-C₆ alkoxy, C₁-C₆ alkyl,and

wherein the C₁-C₂ alkylene group is optionally substituted by oxo; andR¹⁴ is hydrogen, C₁-C₆ alkyl, 5- to 10-membered monocyclic or bicyclicheteroaryl or C₆-C₁₀ monocyclic or bicyclic aryl, wherein each C₁-C₆alkyl, aryl or heteroaryl is optionally independently substituted with 1or 2 R⁶, or a pharmaceutically acceptable salt thereof.
 124. Thecompound of claim 123, wherein A is a 5- to 6-membered monocyclicheteroaryl optionally substituted with 1 or 2 R¹ and optionallysubstituted with 1 or 2 R².
 125. The compound of claim 123, wherein A isany one of: furanyl optionally substituted with 1 or 2 R¹ and optionallysubstituted with 1 or 2 R²; thiophenyl optionally substituted with 1 or2 R¹ and optionally substituted with 1 or 2 R²; oxazolyl optionallysubstituted with 1 or 2 R¹ and optionally substituted with 1 or 2 R²;thiazolyl optionally substituted with 1 or 2 R¹ and optionallysubstituted with 1 or 2 R²; phenyl optionally substituted with 1 or 2 R¹and optionally substituted with 1 or 2 R².
 126. The compound of claim123, wherein m=1 n=0; and wherein A is any one of:


127. The compound of claim 123, wherein m=1 and n=1; and wherein A isany one of:


128. The compound of claim 123, wherein m=2 and n=1; and wherein A isany one of:


129. The compound of claim 123, wherein each of R¹ and R², when present,is independently selected from the group consisting of C₁-C₆ alkyloptionally substituted with one or more hydroxy, halo, oxo, C₁-C₆alkoxy, or NR⁸R⁹; C₃-C₇ cycloalkyl optionally substituted with one ormore hydroxy, halo, oxo, C₁-C₆ alkoxy, C₁-C₆ alkyl, or NR⁸R⁹ wherein theC₁-C₆ salkoxy or C₁-C₆ alkyl is further optionally substituted with oneto three hydroxy, halo, NR⁸R⁹, or oxo; 3- to 7-membered heterocycloalkyloptionally substituted with one or more hydroxy, halo, oxo, C₁-C₆ alkyl,or NR⁸R⁹ wherein the C₁-C₆ alkoxy or C₁-C₆ alkyl is further optionallysubstituted with one to three hydroxy, halo, NR⁸R⁹, or oxo; C₁-C₆haloalkyl; C₁-C₆ alkoxy; C₁-C₆ haloalkoxy; halo; CN; CO—C₁-C₆ alkyl;CO—C₆-C₁₀ aryl; CO (5- to 10-membered heteroaryl); CO₂C₁-C₆ alkyl;CO₂C₃-C₈ cycloalkyl; OCOC₁-C₆ alkyl; OCOC₆-C₁₀ aryl; OCO (5- to10-membered heteroaryl); OCO (3- to 7-membered heterocycloalkyl); C₆-C₁₀aryl; 5- to 10-membered heteroaryl; NH₂; NHC₁-C₆ alkyl; N(C₁-C₆ alkyl)₂;CONR⁸R⁹; SF₅; S(O₂)NR¹¹R¹²; S(O)C₁-C₆ alkyl; and S(O₂)C₁-C₆ alkyl. 130.The compound of claim 123, wherein R¹ is selected from the groupconsisting of 1-hydroxy-2-methylpropan-2-yl; methyl; isopropyl;2-hydroxy-2-propyl; hydroxymethyl; 1-hydroxyethyl; 2-hydroxyethyl;1-hydroxy-2-propyl; 1-hydroxy-1-cyclopropyl; 1-hydroxy-1-cyclobutyl;1-hydroxy-1-cyclopentyl; 1-hydroxy-1-cyclohexyl; morpholinyl;1,3-dioxolan-2-yl; COCH₃; COCH₂CH₃; 2-methoxy-2-propyl;(dimethylamino)methyl; 1-(dimethylamino)ethyl; fluoro; chloro; phenyl;pyridyl; pyrazolyl; S(O₂)CH₃; and S(O₂)NR¹¹R¹².
 131. The compound ofclaim 129, wherein R² is selected from the group consisting of fluoro,chloro, cyano, methyl; methoxy; ethoxy; isopropyl;1-hydroxy-2-methylpropan-2-yl; 2-hydroxy-2-propyl; hydroxymethyl;1-hydroxyethyl; 2-hydroxyethyl; 1-hydroxy-2-propyl;1-hydroxy-1-cyclopropyl; COCH₃; COPh; 2-methoxy-2-propyl;(dimethylamino)methyl; S(O₂)CH₃; and S(O₂)NR¹¹R¹².
 132. The compound ofclaim 123, wherein B is phenyl substituted with 1 or 2 R⁶ and optionallysubstituted with 1, 2, or 3 R⁷.
 133. The compound of claim 132, whereinB is any one of:


134. The compound of claim 123, wherein R³ is hydrogen.
 135. A compoundselected from the group consisting of the compounds below: CompoundStructure 101′

101

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270

113a

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195e

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and pharmaceutically acceptable salts thereof.


136. The compound according to claim 123, wherein the sulfur in themoiety S(═O)(NHR³)═N— has (S) stereochemistry.
 137. The compoundaccording to claim 123, wherein the sulfur in the moiety S(═O)(NHR³)═N—has (R) stereochemistry.
 138. A pharmaceutical composition comprising acompound or salt as claimed in claim 123 and one or morepharmaceutically acceptable excipients.
 139. A method of treating asubject in need thereof having a disease, disorder or condition in whichNLRP3 signaling contributes to the pathology and/or symptoms and/orprogression of the disease disorder or condition, comprisingadministering to the subject an effective amount of a compound accordingto claim
 123. 140. The method according to claim 139, wherein thedisease, disorder or condition is a metabolic disorder, selected fromthe group consisting of Type 2 diabetes, atherosclerosis, obesity andgout; a disease of the central nervous system, selected from the groupconsisting of Alzheimer's disease, multiple sclerosis, AmyotrophicLateral Sclerosis and Parkinson's disease; lung disease, selected fromthe group consisting of asthma, COPD and pulmonary idiopathic fibrosis;liver disease, selected from the group consisting of NASH syndrome,viral hepatitis and cirrhosis; pancreatic disease, selected from thegroup consisting of acute pancreatitis and chronic pancreatitis; kidneydisease, selected from the group consisting of acute kidney injury andchronic kidney injury; intestinal disease, selected from the groupconsisting of Crohn's disease and Ulcerative Colitis; skin disease, thatis psoriasis; musculoskeletal disease, that is scleroderma; a vesseldisorder, that is giant cell arteritis; a disorder of the bones,selected from the group consisting of osteoarthritis, osteoporosis andosteopetrosis disorders; eye disease, selected from the group consistingof glaucoma, macular degeneration, and a disease caused by viralinfection, optionally wherein the diseases caused by viral infection isHIV or AIDS; an autoimmune disease, selected from the group consistingof Rheumatoid Arthritis, Systemic Lupus Erythematosus, AutoimmuneThyroiditis cancer, and aging, optionally wherein the disorder orcondition that is cancer is selected from the group consisting of:myelodysplastic syndromes (MDS); non-small cell lung cancer; acutelymphoblastic leukemia (ALL); Langerhan's cell histiocytosis (LCH);multiple myeloma; promyelocytic leukemia; acute myeloid leukemia (AML);chronic myeloid leukemia (CML); gastric cancer; and lung cancermetastasis.
 141. The method according to claim 139, further comprisingadministering a therapeutically effective amount of an anti-TNFα agentto the subject; optionally wherein: the NLRP3 antagonist is administeredto the subject prior to administration of the anti-TNFα agent to thesubject; or wherein the anti-TNFα agent is administered to the subjectprior to the administration of the NLRP3 antagonist to the subject; orwherein the NLRP3 antagonist and the anti-TNFα agent are administered tothe subject at substantially the same time.